CN1174504A - Piperidines, pyrrolidines and hexahydro -1H -azepines promote release of growth hormone - Google Patents
Piperidines, pyrrolidines and hexahydro -1H -azepines promote release of growth hormone Download PDFInfo
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- CN1174504A CN1174504A CN94194738A CN94194738A CN1174504A CN 1174504 A CN1174504 A CN 1174504A CN 94194738 A CN94194738 A CN 94194738A CN 94194738 A CN94194738 A CN 94194738A CN 1174504 A CN1174504 A CN 1174504A
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Abstract
The present invention is directed to certain piperidine, pyrrolidine, and hexahydro-1H-azepine compounds of general structural formula (I) wherein R1, R3, R4, R5, A, W, X, Y, and n are as defined herein. These compounds promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to treat physiological or medical conditions characterized by a deficiency in growth hormone secretion, such as short stature in growth hormone deficient children, and to treat medical conditions which are improved by the anabolic effects of growth hormone. Growth hormone releasing compositions containing such compounds as the active ingredient thereof are also disclosed.
Description
The cross reference of relevant application
The application is the part continuation application of the common pending application sequence number 08/323,994 of submission on October 17th, 1994, and the latter is again the part continuation application of the common pending application sequence number 08/149,441 of submission on November 9th, 1993; The part continuation application of the common pending application sequence number 08/323,998 that on October 17th, 1994 submitted to, the latter is again the part continuation application of the common pending application sequence number 08/165,149 of December in 1993 submission on the 10th; With the part continuation application of the common pending application sequence number of submitting on October 17th, 1,994 08/323,988, the latter is again the part continuation application of the common pending application sequence number 08/173,449 of December in 1993 submission on the 23rd.
Background of invention
The excretory growth hormone of hypophysis is stimulating the growth of all tissues that can grow in the body.In addition, known growth hormone has following basic influence to the body metabolism process: (1) improves the protein synthesis speed in the health all cells; (2) carbohydrate that reduces in the soma utilizes speed; (3) mobility and the fatty acid of raising free fatty are used to provide energy.It is thick that the growth hormone secretion deficiency can cause various medical science to be lost, faint-hearted as the dwarf.
Known have various ways that growth hormone is discharged.For example, chemicals such as arginine, L-3,4-Dihydroxyphenylalanine (L-DOPA), glucagon, vassopressin and insulin-induced hypoglycemia, and movable as sleep and exercise, can act on hypothalamus in some way, perhaps or reduce the Somat secretion with, or increase known sercretogogue somatotropin releasing factor (GRF) or unknown endogenous growth hormone releasing hormone or the secretion of all these, thereby cause that indirectly hypophysis discharges growth hormone.
Improve in hope under the situation of level of growth hormone, this problem generally is by providing exogenous growth hormone or by administration GRF or a kind of can the stimulating growth hormone generation and/or the peptide compounds that discharges solves.Under any one situation, the peptidyl character of this chemical compound all must make it with the injection system administration therein.At first, the source of growth hormone is the pituitary gland extraction from corpse.This causes product very expensive, and can follow following risk: may pass to this growth hormone receptor with pituitary gland source diseases associated.Can buy the recombinant growth hormone at present, though this no longer follows any risk of communicate illness, but still be a kind of must be with injection system or the administration of per nasal spray pattern, very expensive product.
Developed the chemical compound that other can stimulate endogenous growth hormone to discharge, for example, the peptide of similar Peptidyl compounds relevant or United States Patent (USP) 4,411,890 with GRF.Though these peptides are more much smaller than growth hormone, various protease are remained responsive.The same with most of peptides, the potentiality of its per os biological effectiveness also are low.United States Patent (USP) 5,206 discloses the non-peptide growth hormone cinogenic agent that benzo lactams structure is arranged in 235,5,283,241,5,284,841,5,310,737 and 5,317,017.The compounds of this invention be in various physiological environment, have good stability and also can be non-through intestinal, per nasal or peroral administration, can promote the low-molecular-weight peptide analogues that growth hormone discharges.
Brief summary of the invention
The present invention relates to piperidines, pyrrolidine and hexahydro-1 H-azepines chemical compound that some has the ability that stimulates natural or endogenous growth hormone release.Therefore, these chemical compounds can be used for treating some needs the stimulating growth hormone to produce or excretory disease, for example be used for the hypohormonal human body of spontaneous growth, or be used for goading the food production that causes under the situation bigger, more high yield animal into action and use animal in growth hormone thorn.Therefore, an object of the present invention is to describe these piperidines, pyrrolidine and hexahydro-1 H-azepines chemical compound.A further purpose of the present invention is to describe the preparation process of some chemical compounds like this.A further again purpose is the secretion of describing how to use this compounds to increase humans and animals body inner growth hormone.Of the present invention one more further purpose be to describe to contain these piperidines, pyrrolidine and hexahydro-1 H-azepines chemical compound, be used for the treatment of human body and animal to improve the compositions of growth hormone secretion level.By reading following description, further purpose will become apparent.
Detailed Description Of The Invention
New piperidine of the present invention, pyrrolidine and hexahydro-1H-azepine compound can carry out best description with following structural formula I and pharmaceutically acceptable salt thereof and each diastereomer:
Formula I is wherein:
R
1Be selected from C
1-C
10Alkyl, aryl, aryl (C
1-C
6Alkyl), (C
3-C
7Cycloalkyl) (C
1-C
6Alkyl)-, (C
1-C
5Alkyl)-K-(C
1-C
5Alkyl)-, aryl (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-and (C
3-C
7Cycloalkyl) (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-, wherein K is O, S (O) m, N (R
2) C (O), C (O) N (R
2), OC (O), C (O) O ,-CR
2=CR
2-or-C ≡ C-, wherein aryl is selected from: phenyl, naphthyl, azaindole, pyridine radicals, benzothienyl, benzofuranyl, thiazolyl and benzimidazolyl, R
2With alkyl can be further by 1-9 halogen ,-S (O) mR
2a, a 1-3 OR
2aOr C (O) OR
2aReplace, aryl can be further by 1-3 C
1-C
6Alkyl, a 1-3 halogen, a 1-2 OR
2, the dioxy methylene ,-S (O) mR
2, 1-2-CF
3,-OCF
3, nitro ,-N (R
2) C (O) (R
2) ,-C (O) OR
2,-C (O) N (R
2) (R
2) ,-1H-tetrazolium-5-base ,-SO
2N (R
2) (R
2) ,-N (R
2) SO
2Phenyl or-N (R
2) SO
2R
2Replace;
R
2Be selected from: hydrogen, C
1-C
6Alkyl and C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly be connected to form a C
3-C
8Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
2aBe hydrogen, or the C that is randomly replaced by alkyl
1-C
6Alkyl;
R
3Be selected from: hydrogen ,-(CH
2)
rPhenyl ,-(CH
2)
rNaphthyl ,-C
1-C
10Alkyl ,-C
3-C
7Cycloalkyl, wherein phenyl, naphthyl and C
3-C
7Cycloalkyl ring can be selected from following substituent group by 1-3 and replace: C
1-C
6Alkyl, halogen ,-OR
2,-NHSO
2CF
3,-(CH
2)
rOR
6,-(CH
2)
rN (R
2) (R
6) ,-(CH
2)
r(R
6) ,-(CH
2)
rC (O) OR
2,-(CH
2)
rC (O) OR
6The rOC of ,-(CH2) (O) R2 ,-(CH2) rOC (O) R6 ,-(CH2) rC (O) R2 ,-(CH2) rC (O) R6 ,-(CH
2)
rC (O) N (R
2) (R
2) ,-(CH
2)
rC (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) R
2-(CH
2)
rN (R
2) C (O) R
6The rN of ,-(CH2) (R6) C (O) R2 ,-(CH2) rN (R
6) C (O) R
6,-(CH
2)
rN (R
2) C (O) OR
2,-(CH
2)
rN (R
2) C (O) OR
6,-(CH
2)
rN (R
6) C (O) OR
2,-(CH
2)
rN (R
6) C (O) OR
6,-(CH
2)
rN (R
2) C (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
rN (R
6) C (O) N (R
2) (R
6), (CH
2)
rN (R
2) SO
2R
6,-(CH
2)
rN (R
2) SO
2R
2,-(CH
2)
rN (R
6) SO
2R
2, CH
2)
rN (R
6) SO
2R
6,-(CH
2)
rOC (O) N (R
2) (R
6) ,-(CH
2)
rOC (O) N (R
2) (R
2) ,-(CH
2)
rSO
2N (R
2) (R
6) ,-(CH
2)
rSO
2N (R
2) (R
2), (CH
2)
rSO
2NHC (O) R
6,-(CH
2)
rSO
2NHC (O) R
2,-(CH
2)
rSO
2NHC (O) OR
6,-(CH
2)
rSO
2NHC (O) OR
2,-(CH
2)
rC (O) NHC (O) NR
2,-(CH
2)
rC (O) NHC (O) NR
6,-(CH
2)
rC (O) NHC (O) R
2,-(CH
2)
rCONHC (O) R
6,-(CH
2)
rCONHSO
2R
6,-(CH
2)
rCONHSO
2R
2,-(CH
2)
rCONHSO
2N (R
2) R
2) ,-(CH
2)
rCONHSO
2N (R
2) R
6) ,-(CH
2)
rN (R
2) SO
2N (R
2) R
6) ,-(CH
2)
rN (R
6) SO
2N (R
2) R
6) ,-(CH
2)
rS (O)
mR
6And-(CH
2)
rS (O)
mR
2
R
3aBe hydrogen or the C that randomly replaced by hydroxyl
1-C
6Alkyl;
W is selected from: hydrogen ,-CN ,-C (O) OR
8,-C (O) OR
2,-C (O) O (CH
2)
lAryl ,-C (O) N (R
2) (R
2);-C (O) N (R
2) (R
8) ,-C (O) N (R
2) (CH
2)
lAryl ,-CH
2N (R
2) C (O) R
8-CH
2N (R
2) C (O) (CH
2)
lAryl ,-(CH
2)
rOR
2,-CH (OH) R
2,-CH (OH) (CH
2) aryl ,-C (O) R
2,-C (O) (CH
2) aryl, 1H-tetrazolium-5-base, 5-amino-1,2,4-4-oxadiazole-3-base and 5-methyl isophthalic acid, 2,4-4-oxadiazole-3-base, wherein R
8Be hydrogen, C
1-C
6Alkyl or by OR
2, C (O) OR
2, CON (R
2) (R
2), N (R
2) C (O) R
2, N (R
2) C (O) N (R
2) (R
2) C that replaces
1-C
6Alkyl, and aryl is phenyl, pyridine radicals or 1H-tetrazolium-5-base;
X is selected from: hydrogen ,-C ≡ N ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl ,-(CH
2)
qOR
2,-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl ,-(CH
2)
qOC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qOC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) R
2,-(CH
2)
qC (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qN (R
2) SO
2N (R
2) (R
2) ,-(CH
2)
qS (O)
mR
2And-(CH
2)
qS (O)
m(CH
2)
tAryl, wherein R
2, (CH
2)
q(CH
2)
tGroup can be randomly by 1-2 C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab or 1H-tetrazolium-5-base replaces, and aryl is phenyl, naphthyl, pyridine radicals, thiazolyl or 1H-tetrazolium-5-base group, these groups can be randomly by 1-3 halogen, 1-3 individual-OR
2,-CON (R
2) (R
2) ,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2Or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
10Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
3-C
7Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAlkyl ,-(CH
2)
q-K-(CH
2)
t(contain O, NR
2, S C
3-C
7Cycloalkyl) and-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl), wherein K is O, S (O) m, C (O) NR
2, CH=CH, C ≡ C, N (R
2) C (O), C (O) NR
2, C (O) O or OC (O), and wherein alkyl, R
2, (CH
2)
q(CH
2)
tGroup can be randomly by C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl ,-CONH
2Or the C of carboxylic acid
1-C
4Arrcostab replaces, and aryl is phenyl, naphthyl, pyridine radicals, 1-H-tetrazolium-5-base, thiazolyl, imidazole radicals, indyl, pyrimidine radicals, thiadiazolyl group, pyrazolyl, oxazolyl, isoxazolyl, thienyl, quinolyl, pyrazinyl or isothiazolyl, these groups can be randomly by 1-3 halogen, 1-3-OR
2,-C (O) OR
2,-C (O) N (R
2) (R
2), nitro, cyano group, benzyl, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2Or 1H-tetrazolium-5-base replaces; Its condition is R
3, have at least one not to be hydrogen among W, X and the Y;
R
4And R
5Be hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6Alkyl, wherein substituent group can be 1-5 halogen, a 1-3 hydroxyl, a 1-3 C
1-C
10Alkanoyloxy, a 1-3 C
1-C
6Alkoxyl, phenyl, phenoxy group, 2-furyl, C
1-C
6Alkoxy carbonyl group, S (O) m (C
1-C
6Alkyl); Perhaps R
4And R
5Can lump together formation-(CH
2)
dL
a(CH
2)
e-, wherein La is C (R
2)
2, O, S (O) m or N (R
2), d and e are 1-3 independently, R
2Definition the same;
A is:
Or
Wherein x and y are 0,1,2 or 3 independently;
Z is N-R
6aOr O, wherein R
6aBe hydrogen or C
1-C
6Alkyl;
R
6Be hydrogen, C
1-C
6Alkyl or (CH
2)
vAryl, wherein said alkyl and (CH
2)
vGroup can be randomly by 1-2 O (R
2), S (O) mR
2, 1H-tetrazolium-5-base, C (O) OR
2, C (O) N (R
2) (R
2) or SO
2N (R
2) (R
2), N (R
2) C (O) N (R
2) (R
2) replace, and wherein aryl is phenyl, pyridine radicals, 1H-tetrazolium-5-base, triazolyl, imidazole radicals, thiazolyl, pyrazolyl, thiadiazolyl group, imidazolone-1-base, benzimidazolyl-2 radicals-Ji, triazoline ketone group, randomly by C
1-C
6Alkyl, C
3-C
6Cycloalkyl, amino or hydroxyl replace;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, trifluoromethyl, phenyl, replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, C (O) O (C
1-C
6Alkyl), C
3-C
7Cycloalkyl, N (R
2) (R
2), C (O) N (R
2) (R
2); Perhaps R
7And R
7aCan be independently and R
4And R
5One of in the group or both connect, at end nitrogen-atoms and R
7Or R
7aForm alkylidene bridge between the moieties of group, wherein said bridge contains 1-5 carbon atom; Perhaps R
7And R
7aCan be connected to form a C each other
3-C
7Cycloalkyl;
L is 0,1 or 2;
M is 0,1 or 2;
N is 1,2 or 3;
Q is 0,1,2,3 or 4;
R is 0,1,2 or 3;
T is 0,1,2 or 3;
V is 0,1 or 2.
When n=1, form a pyrrolidine ring, when n=2, form a piperidine ring, and this ring is called as hexahydro-1H-azepines when n=3.
In said structure formula and whole description, following term has the implication of pointing out.
The alkyl of stipulating above is used for being included in those alkyl groups of designated length in the straight or branched configuration, and these groups can randomly contain two keys or triple bond.The example of this class alkyl group has methyl (Me), ethyl (Et), propyl group (Pr), isopropyl (i-Pr), butyl (Bu), sec-butyl (s-Bu), the tert-butyl group (t-Bu), amyl group, isopentyl, hexyl, isohesyl, pi-allyl, propinyl, butadienyl, hexenyl etc.
The alkoxy base of stipulating above is used for being included in those alkoxy bases of designated length in the straight or branched configuration, and these groups can randomly contain two keys or triple bond.The example of this class alkoxy base has, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, amoxy, isoamoxy, hexyloxy, different hexyloxy, allyloxy, third alkynyloxy group, isobutene. oxygen base, hexene oxygen base etc.
" halogen " this term is used for comprising halogen atom fluorine, chlorine, bromine and iodine.
" aryl " this term in the present invention except as otherwise noted, otherwise be to be used for comprising aromatic ring, as be selected from the carbocyclic ring and the heterocyclic aromatic ring of following groups: phenyl, naphthyl, pyridine radicals, 1-H-tetrazolium-5-base, thiazolyl, imidazole radicals, indyl, pyrimidine radicals, thiadiazolyl group, pyrazolyl, oxazolyl, isoxazolyl, thienyl, quinolyl, pyrazinyl or isothiazolyl, these groups can be randomly by 1-3 C
1-C
6Alkyl, a 1-3 halogen, 1-2-OR
2, methylene-dioxy ,-S (O) mR
2, 1-2-CF
3,-OCF
3, nitro ,-N (R
2) C (O) (R
2) ,-C (O) OR
2,-C (O) N (R
2) (R
2) ,-1H-tetrazolium-5-base ,-SO
2N (R
2) (R
2) ,-N (R
2) SO
2Phenyl or-N (R
2) SO
2R
2Replace, wherein R
2By definition herein.
Some term defined above may occur repeatedly in above-mentioned general formula or definition, and when this situation occurring, each term will define independently, and is irrelevant with other term.
First specific embodiments of the present invention is intended to chemical compound and pharmaceutically acceptable salt and each diastereomer of structural formula AI:
Formula AI is wherein:
R
1Be selected from C
1-C
10Alkyl, aryl, aryl (C
1-C
6Alkyl), (C
3-C
7Cycloalkyl) (C
1-C
6Alkyl)-, (C
1-C
5Alkyl)-K-(C
1-C
5Alkyl)-, aryl (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-and (C
3-C
7Cycloalkyl) (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-, wherein K is O, S (O) m, N (R
2) C (O), C (O) N (R
2), OC (O), C (O) O ,-CR
2=CR
2-or-C ≡ C-, wherein aryl is selected from: phenyl, naphthyl, azaindole, pyridine radicals, benzothienyl, benzofuranyl, thiazolyl and benzimidazolyl, R
2With alkyl can be further by 1-9 halogen ,-S (O) mR
2a, a 1-3 OR
2aOr C (O) OR
2aReplace, aryl can be further by 1-3 C
1-C
6Alkyl, a 1-3 halogen, a 1-2 OR
2, the dioxy methylene ,-S (O) mR
2, 1-2-CF
3,-OCF
3, nitro ,-N (R
2) C (O) (R
2) ,-C (O) OR
2,-C (O) N (R
2) (R
2) ,-1H-tetrazolium-5-base ,-SO
2N (R
2) (R
2) ,-N (R
2) SO
2Phenyl or-N (R
2) SO
2R
2Replace;
R
2Be selected from: hydrogen, C
1-C
6Alkyl and C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly be connected to form a C
3-C
8Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
2aBe hydrogen, or the C that is randomly replaced by alkyl
1-C
6Alkyl;
R
3Be selected from: hydrogen ,-(CH
2)
rPhenyl ,-(CH
2)
rNaphthyl ,-C
1-C
10Alkyl ,-C
3-C
7Cycloalkyl, wherein phenyl, naphthyl and C
3-C
7Cycloalkyl ring can be selected from following substituent group by 1-3 and replace: C
1-C
6Alkyl, halogen ,-OR
2,-NHSO
2CF
3,-(CH
2)
rOR
6,-(CH
2)
rN (R
2) (R
6) ,-(CH
2)
r(R
6) ,-(CH
2)
rC (O) OR
2,-(CH
2)
rC (O) OR
6The rOC of ,-(CH2) (O) R2 ,-(CH2) rOC (O) R6 ,-(CH2) rC (O) R2 ,-(CH2) rC (O) R6 ,-(CH
2)
rC (O) N (R
2) (R
2) ,-(CH
2)
rC (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) R
2-(CH
2)
rN (R
2) C (O) R
6The rN of ,-(CH2) (R6) C (O) R2 ,-(CH2) rN (R
6) C (O) R
6,-(CH
2)
rN (R
2) C (O) OR
2,-(CH
2)
rN (R
2) C (O) OR
6,-(CH
2)
rN (R
6) C (O) OR
2,-(CH
2)
rN (R
6) C (O) OR
6,-(CH
2)
rN (R
2) C (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
rN (R
6) C (O) N (R
2) (R
6), (CH
2)
rN (R
2) SO
2R
6,-(CH
2)
rN (R
2) SO
2R
2,-(CH
2)
rN (R
6) SO
2R
2, CH
2)
rN (R
6) SO
2R
6,-(CH
2)
rOC (O) N (R
2) (R
6) ,-(CH
2)
rOC (O) N (R
2) (R
2) ,-(CH
2)
rSO
2N (R
2) (R
6) ,-(CH
2)
rSO
2N (R
2) (R
2), (CH
2)
rSO
2NHC (O) R
6,-(CH
2)
rSO
2NHC (O) R
2,-(CH
2)
rSO
2NHC (O) OR
6,-(CH
2)
rSO
2NHC (O) OR
2,-(CH
2)
rC (O) NHC (O) NR
2,-(CH
2)
rC (O) NHC (O) NR
6,-(CH
2)
rC (O) NHC (O) R
2,-(CH
2)
rCONHC (O) R
6,-(CH
2)
rCONHSO
2R
6,-(CH
2)
rCONHSO
2R
2,-(CH
2)
rCONHSO
2N (R
2) R
2) ,-(CH
2)
rCONHSO
2N (R
2) R
6) ,-(CH
2)
rN (R
2) SO
2N (R
2) R
6) ,-(CH
2)
rN (R
6) SO
2N (R
2) R
6) ,-(CH
2)
rS (O)
mR
6And-(CH
2)
rS (O)
mR
2
R
3aBe hydrogen or the C that randomly replaced by hydroxyl
1-C
6Alkyl;
W is selected from :-CN ,-C (O) OR
8,-C (O) OR
2,-C (O) O (CH
2)
lAryl ,-C (O) N (R
2) (R
2);-C (O) N (R
2) (R
8) ,-C (O) N (R
2) (CH
2)
lAryl ,-CH
2N (R
2) C (O) R
8-CH
2N (R
2) C (O) (CH
2)
lAryl ,-(CH
2)
rOR
2,-CH (OH) R
2,-CH (OH) (CH
2)
lAryl ,-C (O) R
2,-C (O) (CH
2)
lAryl, 1H-tetrazolium-5-base, 5-amino-1,2,4-4-oxadiazole-3-base and 5-methyl isophthalic acid, 2,4-4-oxadiazole-3-base, wherein R
8Be hydrogen, C
1-C
6Alkyl or by OR
2, C (O) OR
2, CON (R
2) (R
2), N (R
2) C (O) R
2, N (R
2) C (O) N (R
2) (R
2) C that replaces
1-C
6Alkyl, and aryl is phenyl, pyridine radicals or 1H-tetrazolium-5-base;
X is selected from: hydrogen ,-C ≡ N ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl ,-(CH
2)
qOR
2,-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl ,-(CH
2)
qOC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qOC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) R
2,-(CH
2)
qC (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qN (R
2) SO
2N (R
2) (R
2) ,-(CH
2)
qS (O)
mR
2And-(CH
2)
qS (O)
m(CH
2)
tAryl, wherein R
2, (CH
2)
q(CH
2)
tGroup can be randomly by 1-2 C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab or 1H-tetrazolium-5-base replaces, and aryl is phenyl, naphthyl, pyridine radicals, thiazolyl or 1H-tetrazolium-5-base group, these groups can be randomly by 1-3 halogen, 1-3 individual-OR
2,-CON (R
2) (R
2) ,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2Or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
10Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
3-C
7Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl ,-(CH
2)
q-K-(CH
2)
t(contain O, NR
2, S C
3-C
7Cycloalkyl) and-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl), wherein K is O, S (O) m, C (O) NR
2, CH=CH, C ≡ C, N (R
2) C (O), C (O) NR
2, C (O) O or OC (O), and wherein alkyl, R
2, (CH
2)
q(CH
2)
tGroup can be randomly by C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl ,-CONH
2Or the C of carboxylic acid
1-C
4Arrcostab replaces, and aryl is phenyl, naphthyl, pyridine radicals, 1-H-tetrazolium-5-base, thiazolyl, imidazole radicals, indyl, pyrimidine radicals, thiadiazolyl group, pyrazolyl, oxazolyl, isoxazolyl, thienyl, quinolyl, pyrazinyl or isothiazolyl, these groups can be randomly by 1-3 halogen, 1-3-OR
2,-C (O) OR
2,-C (O) N (R
2) (R
2), nitro, cyano group, benzyl, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2Or 1H-tetrazolium-5-base replaces;
R
4And R
5Be hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6Alkyl, wherein substituent group can be 1-5 halogen, a 1-3 hydroxyl, a 1-3 C
1-C
10Alkanoyloxy, a 1-3 C
1-C
6Alkoxyl, phenyl, phenoxy group, 2-furyl, C
1-C
6Alkoxy carbonyl group, S (O) m (C
1-C
6Alkyl); Perhaps R
4And R
5Can lump together formation-(CH
2)
dL
a(CH
2)
e-, L wherein
aBe C (R
2)
2, O, S (O) m or N (R
2), d and e are 1-3 independently, R
2Definition the same;
Z is N-R
6aOr O, wherein R
6aBe hydrogen or C
1-C
6Alkyl;
R
6Be hydrogen, C
1-C
6Alkyl or (CH
2)
vAryl, wherein said alkyl and (CH
2)
vGroup can be randomly by 1-2 O (R
2), S (O) mR
2, 1H-tetrazolium-5-base, C (O) OR
2, C (O) N (R
2) (R
2) or SO
2N (R
2) (R
2), N (R
2) C (O) N (R
2) (R
2) replace, and wherein aryl is phenyl, pyridine radicals, 1H-tetrazolium-5-base, triazolyl, imidazole radicals, thiazolyl, pyrazolyl, thiadiazolyl group, imidazolone-1-base, benzimidazolyl-2 radicals-Ji, triazoline ketone group, randomly by C
1-C
6Alkyl, C
3-C
6Cycloalkyl, amino or hydroxyl replace;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, trifluoromethyl, phenyl, replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, C (O) O (C
1-C
6Alkyl), C
3-C
7Cycloalkyl, N (R
2) (R
2), C (O) N (R
2) (R
2); Perhaps R
7And R
7aCan be independently and R
4And R
5One of in the group or both connect, at end nitrogen-atoms and R
7Or R
7aForm alkylidene bridge between the moieties of group, wherein said bridge contains 1-5 carbon atom; Perhaps R
7And R
7aCan be connected to form a C each other
3-C
7Cycloalkyl;
L is 0,1 or 2;
M is 0,1 or 2;
N is 1,2 or 3;
Q is 0,1,2,3 or 4;
R is 0,1,2 or 3;
T is 0,1,2 or 3;
V is 0,1 or 2.
Preferred chemical compound comprises those chemical compounds and pharmaceutically acceptable salt and each diastereomer of formula AIa in this first specific embodiments:
Formula AIa is wherein:
R
1Be selected from: C
1-C
10Alkyl, aryl (C
1-C
4Alkyl)-, C
3-C
6Cycloalkyl (C
1-C
4Alkyl)-, (C
1-C
4Alkyl)-K-(C
1-C
2Alkyl)-, aryl (C
0-C
2Alkyl)-K-(C
1-C
2Alkyl)-and (C
3-C
7Cycloalkyl) (C
0-C
2Alkyl)-K-(C
1-C
2Alkyl)-, wherein K is O, S (O) m, OC (O), C (O) O, and alkyl group can be further by 1-7 halogen, S (O) mR
2, a 1-3 OR
2Or C (O) OR
2Replace, aryl is phenyl, naphthyl, indyl, pyridine radicals, benzothienyl or benzofuranyl, and these groups can be further by 1-2 C
1-C
4Alkyl, a 1-2 halogen, a 1-2 OR
2, S (O) mR
2Or C (O) OR
2Replace;
R
2Be hydrogen, C
1-C
6Alkyl or C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
4-C
7Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
3Be hydrogen or phenyl, phenyl can be randomly at the ortho position by C
1-C
6Alkyl group ,-NHSO
2CF
3,-(CH
2)
r(1H-tetrazolium-5-yl) ,-(CH
2)
rC (O) OR
2, (CH
2)
rC (O) N (R
2) (R
6) replace;
R
3aBe hydrogen, or C
1-C
4Alkyl;
W is-CN ,-C (O) OR
2,-C (O) N (R
2) (R
2) ,-C (O) N (R
2) (CH
2)
lPhenyl, 1H-tetrazolium-5-base, or-(CH
2)
rOR
2
X be hydrogen ,-(CH
2)
qC (O) N (R
2) (R
6), or-(CH
2)
qC (O) OR
2
Y is hydrogen, C
1-C
8Alkyl ,-(CH
2)
tPhenyl ,-(CH
2)
tPyridine radicals or-(CH
2)
tThiazolyl;
R
4And R
5Be hydrogen, C independently
1-C
6Alkyl or the C that replaces
1-C
6Alkyl, wherein substituent group can be 1-5 halogen, a 1-3 hydroxyl, S (O) m (C
1-C
6Alkyl) or phenyl;
R
6Be hydrogen, or C
1-C
6Alkyl;
A is:
Wherein X is 0 or 1;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, trifluoromethyl, phenyl, replacement
1-C
8Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, C (O) O (C
1-C
6Alkyl), C
5-C
7Cycloalkyl, N (R
2) (R
2), C (O) N (R
2) (R
2); Perhaps R
7And R
7aCan be connected to R independently
4Or R
5In one of on, at end nitrogen-atoms and R
7Or R
7aForm alkylidene bridge between the moieties of group, become 5 or 6 yuan of rings; Perhaps R
7And R
7aCan C of interconnection formation
3Cycloalkyl;
L is 0 or 1;
N is 2;
M is 0,1 or 2;
R is 0,1,2 or 3;
Q is 0 or 1;
T is 0 or 1.
Preferred chemical compound comprises those chemical compounds and pharmaceutically acceptable salt and each diastereomer of formula AIb in this first specific embodiments:
Formula AIb is wherein:
R
1Be selected from C
1-C
10Alkyl, aryl (C
1-C
3Alkyl)-and aryl (C
0-C
1Alkyl)-K-(C
1-C
2Alkyl)-, wherein K is O or S (O) m, and aryl is phenyl, pyridine radicals, naphthyl or indyl, and these groups can be randomly by 1-2 C
1-C
4Alkyl, a 1-2 halogen, a 1-2 OR
2, S (O) mR
2Or C (O) OR
2Replace;
R
2Be hydrogen, C
1-C
6Alkyl or C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
5-C
7Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
3Be hydrogen or randomly can be by C at the ortho position
1-C
3Alkyl group, (CH
2)
r(1H-tetrazolium-5-yl) or (CH
2)
rC (O) OR
2The phenyl that replaces;
R
3aBe hydrogen or C
1-C
4Alkyl;
W is-CN ,-C (O) OR
2, or-C (O) N (R
2) (R
2);
X is hydrogen or C (O) OR
2
Y is that hydrogen, benzyl, skin are examined acyl group (picoyl) or thiazolyl methyl;
R
4And R
5Be hydrogen, C independently
1-C
3The C of alkyl, replacement
1-C
3Alkyl, wherein substituent group can be a 1-2 hydroxyl;
R
7And R
7aBe hydrogen or C independently
1-C
4Alkyl;
M is 0,1 or 2;
R is 0,1 or 2.
Most preferred growth hormone releasing compounds comprises following compounds and pharmaceutically acceptable salt and each diastereomer in this first specific embodiments:
Second specific embodiments of the present invention is intended to chemical compound and pharmaceutically acceptable salt and each diastereomer of structural formula BI:
Formula BI is wherein:
R
1Be selected from following groups: C
1-C
10Alkyl, aryl, aryl (C
1-C
6Alkyl), (C
3-C
7Cycloalkyl) (C
1-C
6Alkyl)-, (C
1-C
5Alkyl)-K-(C
1-C
5Alkyl)-, aryl (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-and (C
3-C
7Cycloalkyl) (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-, wherein K is O, S (O) m, N (R
2) C (O), C (O) N (R
2), OC (O), C (O) O ,-CR
2=CR
2-, or-C ≡ C-, wherein aryl is selected from: phenyl, naphthyl, indyl, azaindolyl, pyridine radicals, benzothienyl, benzofuranyl, thiazolyl and benzimidazolyl, and R
2With alkyl can be further by 1-9 halogen, S (O) mR
2a, a 1-3 OR
2aOr C (O) OR
2aReplace, aryl can be further by 1-3 C
1-C
6Alkyl, a 1-3 halogen, a 1-2 OR
2, methylene-dioxy ,-S (O) mR
2, 1-2-CF
3,-OCF
3, nitro ,-N (R
2) C (O) (R
2) ,-C (O) OR
2,-C (O) N (R
2) (R
2) ,-1H-tetrazolium-5-base ,-SO
2N (R
2) (R
2) ,-N (R
2) SO
2Phenyl, or-N (R
2) SO
2R
2Replace;
R
2Be selected from: hydrogen, C
1-C
6Alkyl and C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
3-C
8Cyclic ring randomly contains aerobic, sulfur or NR
3a, R wherein
3aBe hydrogen or C
1-C
6Alkyl randomly can be replaced by hydroxyl;
R
2aBe hydrogen or the C that randomly replaced by hydroxyl
1-C
6Alkyl;
R
3Be selected from :-(CH
2)
rPhenyl ,-(CH
2)
rNaphthyl ,-C
1-C
10Alkyl ,-C
3-C
7Cycloalkyl, and phenyl, naphthyl and C
3-C
7The ring of cycloalkyl can further be selected from following substituent group by 1-3 and replace: C
1-C
6Alkyl, halogen ,-OR
2,-NHSO
2CF
3,-C (CH
2)
rOR
6,-(CH
2)
rN (R
2) (R
6),-(CH
2)
r(R
6) ,-(CH
2)
rC (O) OR
2,-(CH
2)
rC (O) OR
6The rOC of ,-(CH2) (O) R2 ,-(CH2) rOC (O) R6 ,-(CH2) rC (O) R2 ,-(CH2) rC (O) R6 ,-(CH
2)
rC (O) N (R
2) (R
2) ,-(CH
2)
rC (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) R
2-(CH
2)
rN (R
2) C (O) R
6The rN of ,-(CH2) (R6) C (O) R2 ,-(CH2) rN (R
6) C (O) R
6,-(CH
2)
rN (R
2) C (O) OR
2,-(CH
2)
rN (R
2) C (O) OR
6,-(CH
2)
rN (R
6) C (O) OR
2,-(CH
2)
rN (R
6) C (O) OR
6,-(CH
2)
rN (R
2) C (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
rN (R
6) C (O) N (R
2) (R
6), (CH
2)
rN (R
2) SO
2R
6,-(CH
2)
rN (R
2) SO
2R
2,-(CH
2)
rN (R
6) SO
2R
2, CH
2)
rN (R
6) SO
2R
6,-(CH
2)
rOC (O) N (R
2) (R
6) ,-(CH
2)
rOC (O) N (R
2) (R
2) ,-(CH
2)
rSO
2N (R
2) (R
6) ,-(CH
2)
rSO
2N (R
2) (R
2), (CH
2)
rSO
2NHC (O) R
6,-(CH
2)
rSO
2NHC (O) R
2,-(CH
2)
rSO
2NHC (O) OR
6,-(CH
2)
rSO
2NHC (O) OR
2,-(CH
2)
rC (O) NHC (O) NR
2,-(CH
2)
rC (O) NHC (O) NR
6,-(CH
2)
rC (O) NHC (O) R
2,-(CH
2)
rCONHC (O) R
6,-(CH
2)
rCONHSO
2R
6,-(CH
2)
rCONHSO
2R
2,-(CH
2)
rCONHSO
2N (R
2)R
2),-(CH
2)
rCONHSO
2N (R
2) R
6) ,-(CH
2)
rN (R
2) SO
2N (R
2) R
6) ,-(CH
2)
rN (R
6) SO
2N (R
2) R
6) ,-(CH
2)
rS (O)
mR
6And-(CH
2)
rS (O)
mR
2
R
3aBe hydrogen, or the C that is randomly replaced by hydroxyl
1-C
6Alkyl;
X is selected from: hydrogen ,-C ≡ N ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl ,-(CH
2)
qOR
2,-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl ,-(CH
2)
qOC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qOC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) R
2,-(CH
2)
qC (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qN (R
2) SO
2N (R
2) (R
2) ,-(CH
2)
qS (O)
mR
2And-(CH
2)
qS (O)
m(CH
2)
tAryl, wherein R
2, (CH
2)
q(CH
2)
tGroup can be randomly by 1-2 C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab, or the 1H-tetrazolium-the 5-base replaces, and aryl is phenyl, naphthyl, pyridine radicals, thiazolyl or 1H-tetrazolium-5-base, these groups can be randomly by 1-3 halogen, a 1-3 OR
2,-CON (R
2) (R
2) ,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
10Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
3-C
7Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl ,-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl contains O, NR
2, S) and-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl), wherein K is O, S (O) m, C (O) NR
2, CH=CH, C ≡ C, N (R
2) C (O), C (O) NR
2, C (O) O or OC (O), and wherein alkyl, R
2, (CH
2)
q(CH
2)
tGroup can be randomly by C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl ,-CONH
2Or carboxylic acid C
1-C
4Arrcostab replaces, and aryl is phenyl, naphthyl, pyridine radicals, 1H-tetrazolium-5-base, thiazolyl, imidazole radicals, indyl, pyrimidine radicals, thiadiazolyl group, pyrazolyl, oxazolyl, isoxazolyl, thienyl, quinolyl, pyrazinyl or isothiazolyl, and these groups can be randomly by 1-3 halogen, a 1-3 OR
2, 1-2-N (R
2) (R
2) ,-C (O) OR
2,-C (O) N (R
2) (R
2), nitro, NHC (O) R
2, cyano group, benzyl, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
R
4And R
5Be hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6Alkyl, wherein substituent group can be 1-5 halogen, a 1-3 hydroxyl, a 1-3 C
1-C
10Alkanoyloxy, a 1-3 C
1-C
6Alkoxyl, phenyl, phenoxy group, 2-furyl, C
1-C
6Alkoxy carbonyl group, S (O) m (C
1-C
6Alkyl); Perhaps R
4And R
5Can lump together formation-(CH
2)
dL
a(CH
2)
e-, L wherein
aBe C (R
2)
2, O, S (O) m or N (R
2), d and e are 1-3 independently, R
2Definition the same;
Wherein x and y are 0,1,2 or 3 independently;
Z is N-R
6aOr O, R here
6aBe hydrogen or C
1-C
6Alkyl;
R
6Be hydrogen, C
1-C
6Alkyl, or (CH
2)
rAryl, wherein alkyl and (CH
2)
vGroup can be randomly by 1-2 OR
2, S (O) mR
2, 1H-tetrazolium-5-base, C (O) OR
2, C (O) N (R
2) (R
2) or SO
2N (R
2) (R
2), N (R
2) C (O) N (R
2) (R
2) replace, and wherein aryl is phenyl, pyridine radicals, 1H-tetrazolium-5-base, triazolyl, imidazole radicals, thiazolyl, pyrazolyl, thiadiazolyl group, imidazolone-1-base, oxadiazole base, benzimidazolyl-2 radicals-Ji, triazoline ketone group, randomly by C
1-C
6Alkyl, C
3-C
6Cycloalkyl, amino or hydroxyl replace;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, trifluoromethyl, phenyl, replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, C (O) OR
2, C
3-C
7Cycloalkyl, C (R
2) (R
2), C (O) N (R
2) (R
2); Perhaps R
7And R
7aCan be independently and R
4And R
5One or two connection in the group is at end nitrogen-atoms and R
7Or R
7aForm alkylidene bridge between the moieties of group, wherein this bridge contains 1-5 carbon atom; Perhaps R
7And R
7aCan C of interconnection formation
3-C
7Cycloalkyl;
M is 0,1 or 2;
N is 1,2 or 3;
Q is 0,1,2,3 or 4;
R is 0,1,2 or 3;
T is 0,1,2 or 3;
V is 0,1 or 2.
Preferred chemical compound comprises chemical compound and pharmaceutically acceptable salt and each diastereomer of formula BIa in second specific embodiments:
Formula BIa is wherein:
R
1Be selected from following groups: C
1-C
10Alkyl, aryl (C
1-C
4Alkyl)-, (C
3-C
6Cycloalkyl) (C
1-C
4Alkyl)-, (C
1-C
4Alkyl)-K-(C
1-C
2Alkyl)-, aryl (C
0-C
2Alkyl)-K-(C
1-C
2Alkyl)-and (C
3-C
7Cycloalkyl) (C
0-C
2Alkyl)-K-(C
1-C
2Alkyl)-, wherein K is O, S (O) m, OC (O) or C (O) O, wherein alkyl can be further by 1-7 halogen, S (O) mR
2, a 1-3 OR
2Or C (O) OR
2Replace, aryl is phenyl, naphthyl, indyl, pyridine radicals, benzimidazolyl, azaindolyl, benzothienyl or benzofuranyl, these aryl can be further by 1-2 C
1-C
4Alkyl, a 1-2 halogen, a 1-2 OR
2,-S (O) mR
2, or-C (O) OR
2Replace;
R
2Be hydrogen, C
1-C
6Alkyl and C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
4-C
7Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
3Be phenyl, it can be randomly by 1-2 C
1-C
6Alkyl, a 1-2 halogen or 1-2 OR
2Replace, and can further be selected from following substituent group at its ortho position and replace :-NHSO
2CF
3,-(CH
2)
rOR
6,-(CH
2)
rN (R
2) (R
6),-(CH
2)
r(R
6) ,-(CH
2)
rC (O) OR
2,-(CH
2)
rC (O) OR
6The rOC of ,-(CH2) (O) R2 ,-(CH
2)
rOC (O) R
6,-(CH
2)
rC (O) R
2,-(CH
2)
rC (O) R
6,-(CH
2)
rC (O) N (R
2) (R
2) ,-(CH
2)
rC (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) R
2-(CH
2)
rN (R
2) C (O) R
6,-(CH
2)
rN (R
6) C (O) R
2,-(CH
2)
rN (R
6) C (O) R
6,-(CH
2)
rN (R
2) C (O) OR
2,-(CH
2)
rN (R
2) C (O) OR
6,-(CH
2)
rN (R
6) C (O) OR
2,-(CH
2)
rN (R
6) C (O) OR
6,-(CH
2)
rN (R
2) C (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
rN (R
6) C (O) N (R
2) (R
6), (CH
2)
rN (R
2) SO
2R
6,-(CH
2)
rN (R
2) SO
2R
2,-(CH
2)
rN (R
6) SO
2R
2, CH
2)
rN (R
6) SO
2R
6,-(CH
2)
rOC (O) N (R
2) (R
6) ,-(CH
2)
rOC (O) N (R
2) (R
2) ,-(CH
2)
rSO
2N (R
2) (R
6) ,-(CH
2)
rSO
2N (R
2) (R
2), (CH
2)
rSO
2NHC (O) R
6,-(CH
2)
rSO
2NHC (O) R
2,-(CH
2)
rSO
2NHC (O) OR
6,-(CH
2)
rSO
2NHC (O) OR
2,-(CH
2)
rC (O) NHC (O) NR
2,-(CH
2)
rC (O) NHC (O) NR
6,-(CH
2)
rC (O) NHC (O) R
2,-(CH
2)
rCONHC (O) R
6,-(CH
2)
rCONHSO
2R
6,-(CH
2)
rCONHSO
2R
2,-(CH
2)
rCONHSO
2N (R
2) R
2) ,-(CH
2)
rCONHSO
2N (R
2) R
6) ,-(CH
2)
rN (R
2) SO
2N (R
2) R
6) ,-(CH
2)
rN (R
6) SO
2N (R
2) R
6) ,-(CH
2)
rS (O)
mR
6And-(CH
2)
rS (O)
mR
2
R
3aBe hydrogen, or C
1-C
4Alkyl;
X is selected from: hydrogen ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl, (CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl ,-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl ,-(CH
2)
qS (O) mR
2And-(CH
2)
qS (O) m (CH
2)
tAryl, wherein R
2Group can be randomly by hydroxyl, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab, or tetrazole radical replacement, and aryl is phenyl, naphthyl, pyridine radicals or 1H-tetrazole radical; These groups can be randomly by 1-2 halogen, a 1-2 OR
2,-CONH
2,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
8Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
5-C
6Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl ,-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl contains O, NR
2, or S) and-(CH
2)
q-K-(CH
2)
t(C
5-C
6Cycloalkyl), wherein K be O or S (O) m and wherein the alkyl gene can be randomly by hydroxyl, carboxyl ,-CONH
2, carboxylic acid C
1-C
4Arrcostab or 1H-tetrazolium-5-base replaces, and aryl is phenyl, naphthyl, pyridine radicals, 1H-tetrazole radical, thiazolyl, imidazole radicals, pyrimidine radicals, thiadiazolyl group, pyrazolyl, oxazolyl, isoxazolyl or thienyl, and these groups can be randomly by 1-3 halogen, a 1-3 OR
2, 1-2-N (R
2) (R
2) ,-C (O) OR
2,-C (O) N (R
2) (R
2), cyano group, a 1-2 C
1-C
4Alkyl, benzyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
R
4And R
5Be hydrogen, C independently
1-C
6Alkyl, or the C that replaces
1-C
6Alkyl, wherein substituent group can be 1-5 halogen, a 1-3 hydroxyl, S (O) m (C
1-C
6Alkyl) or phenyl;
R
6Be hydrogen, C
1-C
6Alkyl, or (CH
2)
vAryl, wherein alkyl and (CH
2)
vGroup can be randomly by 1-2 O (R
2), S (O) mR
2, C (O) OR
2, C (O) N (R
2) (R
2) or SO
2N (R
2) (R
2), N (R
2) C (O) N (R
2) (R
2) replace, and wherein aryl can be phenyl, pyridine radicals, 1H-tetrazolium-5-base, triazolyl, imidazole radicals, thiazolyl, oxadiazole base, pyrazolyl, thiadiazolyl group, phenyl and imidazoles-2-base, randomly by C
1-C
6Alkyl, C
3-C
6Cycloalkyl, amino or hydroxyl replace;
A is:
Wherein X is 0, or 1;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, trifluoromethyl, phenyl, replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, C (O) OR
2, C
5-C
7Cycloalkyl, N (R
2) (R
2), C (O) N (R
2) (R
2); Perhaps R
7And R
7aCan be independently and R
4And R
5A connection in the group is at end nitrogen-atoms and R
7Or R
7aForm alkylidene bridge between the moieties of group, form one 5 yuan or 6 yuan of rings; Perhaps R
7And R
7aCan C of interconnection formation
3Cycloalkyl;
N is 2;
M is 0,1 or 2;
R is 0,1,2 or 3;
Q is 0,1,2 or 3;
T is 0,1,2 or 3;
V is 0,1 or 2.
Preferred chemical compound comprises chemical compound and pharmaceutically acceptable salt and each diastereomer of formula BIb in second specific embodiments:
Formula BIb is wherein:
R
1Be selected from following groups: C
1-C
10Alkyl, aryl (C
1-C
3Alkyl)-, (C
3-C
7Cycloalkyl) (C
1-C
3Alkyl)-and aryl (C
0-C
1Alkyl)-K-(C
1-C
2Alkyl)-, wherein K is O or S (O) m, and aryl specifically is phenyl, pyridine radicals, naphthyl, indyl, azaindolyl or benzimidazolyl, and these groups can be randomly by 1-2 C
1-C
4Alkyl, a 1-2 halogen, a 1-2 OR
2, S (O) mR
2,-C (O) OR
2Replace;
R
2Be hydrogen, C
1-C
6Alkyl and C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
5-C
7Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
3Be phenyl, they can be randomly by 1-2 C
1-C
6Alkyl, a 1-2 halogen or 1-2 OR
2Replace, and can further be selected from following substituent group at its ortho position and replace :-NHSO
2CF
3,-(CH
2)
rOR
6,-(CH
2)
rN (R
2) (R
6) ,-(CH
2)
r(R
6) ,-(CH
2)
rC (O) OR
6,-(CH
2)
rOC (O) R
2,-(CH
2)
rOC (O) R
6,-(CH
2)
rC (O) R
2,-(CH
2)
rC (O) R
6,-(CH
2)
rC (O) N (R
2) (R2) ,-(CH
2)
rC (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) R
2-(CH
2)
rN (R
2) C (O) R
6The rN of ,-(CH2) (R6) C (O) R2 ,-(CH2) rN (R
6) C (O) R
6,-(CH
2)
rN (R
2) C (O) OR
2,-(CH
2)
rN (R
2) C (O) OR
6,-(CH
2)
rN (R
6) C (O) OR
2,-(CH
2)
rN (R
6) C (O) OR
6,-(CH
2)
rN (R
2) C (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
rN (R
6) C (O) N (R
2) (R
6), (CH
2)
rN (R
2) SO
2R
6,-(CH
2)
rN (R
2) SO
2R
2,-(CH
2)
rN (R
6) SO
2R
2, CH
2)
rN (R
6) SO
2R
6,-(CH
2)
rOC (O) N (R
2) (R
6) ,-(CH
2)
rOC (O) N (R
2) (R
2) ,-(CH
2)
rSO
2N (R
2) (R
6) ,-(CH
2)
rSO
2N (R
2) (R
2), (CH
2)
rSO
2NHC (O) R
6,-(CH
2)
rSO
2NHC (O) R
2,-(CH
2)
rSO
2NHC (O) OR
6,-(CH
2)
rSO
2NHC (O) OR
2,-(CH
2)
rCONHSO
2R
6,-(CH
2)
rCONHSO
2R
2,-(CH
2)
rS (O)
mR
6And-(CH
2)
rS (O)
mR
2
R
3aBe hydrogen, or C
1-C
4Alkyl;
X is selected from: hydrogen ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl-(CH
2)
qS (O)
mR
2And-(CH
2)
qS (O) m (CH
2)
tAryl, wherein R
2Group can be randomly by hydroxyl, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab, or tetrazole radical replacement, and aryl is phenyl, naphthyl or pyridine radicals, these groups can be further by 1-2 halogen, a 1-2 OR
2,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
8Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
5-C
7Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl and-(CH
2)
q-K-(CH
2)
t(C
5-C
6Cycloalkyl), wherein K is S (O) m, and wherein alkyl group can be randomly by hydroxyl, carboxyl ,-CONH
2, carboxylic acid C
1-C
4Arrcostab 1H-tetrazolium-the 5-base replaces, and aryl specifically is phenyl, naphthyl, pyridine radicals, thiazolyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl or imidazole radicals, and these groups can be randomly by 1-2 halogen, a 1-2 OR
2, 1-2-N (R
2) (R
2) ,-CO (OR
2), a 1-2 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
R
4And R
5Be hydrogen, C independently
1-C
4The C of alkyl, replacement
1-C
3Alkyl, wherein substituent group can be a 1-2 hydroxyl;
R
6Be hydrogen, C
1-C
6Alkyl, or (CH
2)
vAryl, wherein C
1-C
6Alkyl and (CH
2)
vAromatic yl group can be randomly by 1-2 O (R
2), S (O) mR
2, C (O) OR
2, C (O) N (R
2) (R
2) or SO
2N (R
2) (R
2), N (R
2) C (O) N (R
2) (R
2) replace, and wherein aryl specifically is phenyl, pyridine radicals, 1H-tetrazolium-5-base, triazolyl, imidazole radicals, thiazolyl, oxadiazole base, pyrazolyl, thiadiazolyl group, benzimidazolyl-2 radicals-Ji, randomly by C
1-C
6Alkyl, C
3-C
6Cycloalkyl, amino or hydroxyl replace;
A is
Wherein X is 0 or 1;
R
7And R
7aBe hydrogen, C independently
1-C
2The C of alkyl, phenyl, replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, perhaps R
7And R
7aCan C of interconnection independently formation
3Cycloalkyl;
M is 0,1 or 2;
R is 0,1,2 or 3;
Q is 0,1,2 or 3;
T is 0,1,2 or 3;
V is 0,1 or 2.
Preferred chemical compound is chemical compound and pharmaceutically acceptable salt and each diastereomer of Formula B Ic in this second specific embodiments:
Formula BIc is wherein:
R
2Be hydrogen, C
1-C
6Alkyl, or C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
5-C
7Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
3Be by being selected from the optional phenyl that replaces of a following substituent group :-NHSO at the ortho position
2CF
3,-(CH
2)
rOR
6,-(CH
2)
r(R
6) ,-(CH
2)
rC (O) OR
2,-(CH
2)
rC (O) OR
6The rOC of ,-(CH2) (O) R2 ,-(CH2) rOC (O) R6 ,-(CH2) rC (O) R2 ,-(CH2) rC (O) R6 ,-(CH
2)
rC (O) N (R
2) (R
2) ,-(CH
2)
rC (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) R
2-(CH
2)
rN (R
2) C (O) R
6,-(CH
2)
rN (R
6) C (O) R
2,-(CH
2)
rN (R
6) C (O) R
6,-(CH
2)
rN (R
2) C (O) OR
2,-(CH
2)
rN (R
2) C (O) OR
6,-(CH
2)
rN (R
6) C (O) OR
2,-(CH
2)
rN (R
6) C (O) OR
6,-(CH
2)
rN (R
2) C (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
rN (R
6) C (O) N (R
2) (R
6), (CH
2)
rN (R
2) SO
2R
6,-(CH
2)
rN (R
2) SO
2R
2,-(CH
2)
rN (R
6) SO
2R
2, CH
2)
rN (R
6) SO
2R
6,-(CH
2)
rOC (O) N (R
2) (R
6) ,-(CH
2)
rOC (O) N (R
2) (R
2) ,-(CH
2)
rSO
2N (R
2) (R
6) ,-(CH
2)
rSO
2N (R
2) (R
2), (CH
2)
rSO
2NHC (O) R
6,-(CH
2)
rSO
2NHC (O) R
2,-(CH
2)
rSO
2NHC (O) OR
6,-(CH
2)
rSO
2NHC (O) OR
2,-(CH
2)
rCONHSO
2R
6,-(CH
2)
rCONHSO
2R
2,-(CH
2)
rS (O)
mR
6And-(CH
2)
rS (O)
mR
2
R
3aBe hydrogen or C
1-C
4Alkyl;
Y is selected from following groups: hydrogen, C
1-C
8Alkyl, (CH
2)
tAryl ,-(CH
2)
qC
5-C
7Cycloalkyl ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl, or-(CH
2)
q-K-(CH
2)
t(C
5-C
6Cycloalkyl), wherein K is S (O) m, and wherein alkyl group can be randomly by hydroxyl, carboxyl, CONH
2, carboxylic acid C
1-C
4Arrcostab or 1H-tetrazolium-5-base replaces, and wherein aryl specifically is phenyl, naphthyl, pyridine radicals, thiazolyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl group, pyrimidine radicals or imidazole radicals, and these groups randomly can be by 1-2 halogen, a 1-2 OR
2, CO (OR)
2, a 1-2 C
1-C
4Alkyl, S (O) mR
2Or 1H-tetrazolium-5-base replaces;
R
4And R
5Be independently selected from following groups:
R
6Be hydrogen, C
1-C
6Alkyl or (CH
2)
vAryl, wherein alkyl and (CH
2)
vGroup can be randomly by halogen, OR
2, N (R
2) (R
2), C
3-C
6Cycloalkyl, 1H-tetrazolium-5-base, C (O) OR
2, C (O) N (R
2) (R
2), SO
2N (R
2) (R
2) or N (R
2) C (O) N (R
2) (R
2) replace, wherein aryl is selected from following aromatic group and orientation isomer thereof:
Wherein these aromatic groups can be randomly by C
1-C
2Alkyl ,-N (R
2) (R
2) or the hydroxyl replacement;
M is 0,1 or 2;
R is 0,1,2 or 3;
Q is 0 or 1;
T is 0 or 1;
V is 0 or 1.
Preferred examples for compounds comprises following compounds and pharmaceutically acceptable salt and each diastereomer (if not explanation in addition) in this second specific embodiments:
Cisd
1,
Cisd
2,
Transd
1,
Transd
2 Cisd
1,
Cisd
2,
Transd
1,
Transd
2
Cisd
1,
Cisd
2,
Transd
1,
Transd
2 Cisd
1,
Cisd
2,
Transd
1,
Transd
2
Above shown in all these preferred chemical compounds all contain at least 1 asymmetric center, according in the substituent characteristic different molecular on the piperidine ring extra asymmetric center being arranged.Each such asymmetric center will produce two optical isomers, therefore, be intended that all these optical isomers, independent and, pure or partially purified optical isomer, its racemic mixture or non-enantiomer mixture all should comprise within the scope of the invention.
Most preferred in this second specific embodiments comprises following compounds and pharmaceutically acceptable salt and each diastereomer (as not explanation in addition):
Cisd
1,
Cisd
2 Cisd
1,
Cisd
2
Cisd
1,
Cisd
2 Cisd
1,
Cisd
2
The 3rd specific embodiments of the present invention is intended to chemical compound and pharmaceutically acceptable salt and each diastereomer of structural formula CI:
Formula CI is wherein:
R
1Be selected from following groups: C
1-C
10Alkyl, aryl, aryl (C
1-C
6Alkyl), (C
3-C
7Cycloalkyl) (C
1-C
6Alkyl)-, (C
1-C
5Alkyl)-K-(C
1-C
5Alkyl)-, aryl (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-and (C
3-C
7Cycloalkyl) (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-, wherein K is O, S (O) m, N (R
2) C (O), C (O) N (R
2), OC (O), C (O) O ,-CR
2=CR
2-, or-C ≡ C-, wherein aryl is selected from: phenyl, naphthyl, indyl, azaindolyl, pyridine radicals, benzothienyl, benzofuranyl, thiazolyl and benzimidazolyl, and R
2With alkyl can be further by 1-9 halogen, S (O) mR
2a, a 1-3 OR
2aOr C (O) OR
2aReplace, aryl can be further by 1-3 C
1-C
6Alkyl, a 1-3 halogen, a 1-2 OR
2, methylene-dioxy ,-S (O) mR
2, 1-2-CF
3,-OCF
3, nitro ,-N (R
2) C (O) (R
2) ,-C (O) OR
2,-C (O) N (R
2) (R
2) ,-1H-tetrazolium-5-base ,-SO
2N (R
2) (R
2) ,-N (R
2) SO
2Phenyl, or-N (R
2) SO
2R
2Replace;
R
2Be selected from: hydrogen, C
1-C
6Alkyl and C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
3-C
8Cyclic ring randomly contains aerobic, sulfur or NR
3a, R wherein
3aBe hydrogen or C
1-C
6Alkyl randomly can be replaced by hydroxyl;
R
2aBe hydrogen or the C that randomly replaced by hydroxyl
1-C
6Alkyl;
X is selected from: hydrogen ,-C ≡ N ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl ,-(CH
2)
qOR
2,-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl ,-(CH
2)
qOC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qOC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) R
2,-(CH
2)
qC (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qN (R
2) SO
2N (R
2) (R
2) ,-(CH
2)
qS (O) mR
2And-(CH
2)
qS (O) m (CH
2) aryl, wherein R
2, (CH
2)
q(CH
2)
tGroup can be randomly by 1-2 C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab, or the 1H-tetrazolium-the 5-base replaces, and aryl is phenyl, naphthyl, pyridine radicals, thiazolyl or 1H-tetrazolium-5-base, these groups can be randomly by 1-3 halogen, a 1-3 OR
2,-CON (R
2) (R
2) ,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
10Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
3-C
7Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl ,-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl contains O, NR
2, S) and-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl), wherein K is O, S (O) m, C (O) NR
2, CH=CH, C ≡ C, N (R
2) C (O), C (O) NR
2, C (O) O or OC (O), and wherein alkyl, R
2, (CH
2)
q(CH
2)
tGroup can be randomly by C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl ,-CONH
2Or carboxylic acid C
1-C
4Arrcostab replaces, and aryl is phenyl, naphthyl, pyridine radicals, 1H-tetrazolium-5-base, thiazolyl, imidazole radicals, indyl, pyrimidine radicals, thiadiazolyl group, pyrazolyl, oxazolyl, isoxazolyl, thienyl, quinolyl, pyrazinyl or isothiazolyl, and these groups can be randomly by 1-3 halogen, a 1-3 OR
2,-C (O) OR
2,-C (O) N (R
2) (R
2), nitro, cyano group, benzyl, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replacement, its condition is if X is a hydrogen, then Y can not be hydrogen;
R
4And R
5Be hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6Alkyl, wherein substituent group can be 1-5 halogen, a 1-3 hydroxyl, a 1-3 C
1-C
10Alkanoyloxy, a 1-3 C
1-C
6Alkoxyl, phenyl, phenoxy group, 2-furyl, C
1-C
6Alkoxy carbonyl group, S (O) m (C
1-C
6Alkyl); Perhaps R
4And R
5Can lump together formation-(CH
2)
dL
a(CH
2)
e-, L wherein
aBe-C (R
2)
2-, O, S (O) m or N (R
2), d and e are 1-3 independently, R
2Definition the same;
Wherein x and y are 0,1,2 or 3 independently;
Z is N-R
6aOr O, R here
6aBe hydrogen or C
1-C
6Alkyl;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, trifluoromethyl, phenyl or replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, C (O) OR
2, C
3-C
7Cycloalkyl, C (R
2) (R
2), C (O) N (R
2) (R
2); Perhaps R
7And R
7aCan be independently and R
4And R
5One or two connection in the group is at end nitrogen-atoms and R
7Or R
7aForm alkylidene bridge between the moieties of group, wherein this bridge contains 1-5 carbon atom; Perhaps R
7And R
7aCan C of interconnection formation
3-C
7Cycloalkyl;
M is 0,1 or 2;
N is 1,2 or 3;
Q is 0,1,2,3 or 4;
T is 0,1,2 or 3.
Preferred chemical compound comprises chemical compound and pharmaceutically acceptable salt and each diastereomer of general formula CIa in the 3rd specific embodiments:
Formula CIa is wherein:
R
1Be selected from following groups: C
1-C
10Alkyl, aryl (C
1-C
4Alkyl)-, (C
3-C
6Cycloalkyl) (C
1-C
4Alkyl)-, (C
1-C
4Alkyl)-K-(C
1-C
2Alkyl)-, aryl (C
0-C
2Alkyl)-K-(C
1-C
2Alkyl)-and (C
3-C
7Cycloalkyl) (C
0-C
2Alkyl)-K-(C
1-C
2Alkyl)-, wherein K is O, S (O) m, OC (O), or C (O) O, alkyl can be further by 1-7 halogen, S (O) mR
2a, a 1-3 OR
2Or C (O) OR
2Replace, aryl is phenyl, naphthyl, indyl, pyridine radicals, benzimidazolyl, azaindolyl, benzothienyl or benzofuranyl, and these aryl can be further by 1-2 C
1-C
4Alkyl, a 1-2 halogen, a 1-2 OR
2, S (O) mR
2,-C (O) OR
2Replace;
R
2Be hydrogen, C
1-C
6Alkyl and C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
4-C
7Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
3aBe hydrogen or C
1-C
4Alkyl;
X is selected from: hydrogen ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl ,-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl ,-(CH
2)
qS (O) mR
2And-(CH
2)
qS (O) m (CH
2)
tAryl, wherein R
2Group can be randomly by hydroxyl, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab, or tetrazole radical replacement, and aryl is phenyl, naphthyl, pyridine radicals or 1H-tetrazole radical, these groups can be randomly by 1-2 halogen, a 1-2 OR
2,-CONH
2,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
8Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
5-C
6Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl ,-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl contains O, NR
2, S) and-(CH
2)
q-K-(CH
2)
t(C
5-C
6Cycloalkyl), wherein K is O or S (O) m, and wherein alkyl group can be randomly by hydroxyl, carboxyl ,-CONH
2, carboxylic acid C
1-C
4Arrcostab or 1H-tetrazolium-5-base replaces, and aryl is phenyl, naphthyl, pyridine radicals, 1H-tetrazolium-5-base, thiazolyl, imidazole radicals, indyl, pyrimidine radicals, thiadiazolyl group, pyrazolyl, oxazolyl, isoxazolyl or thienyl, and these groups can be randomly by 1-3 halogen, a 1-3 OR
2,-C (O) OR
2,-C (O) N (R
2) (R
2), cyano group, a 1-2 C
1-C
4Alkyl, benzyl-S (O) mR
2, or 1H-tetrazolium-5-base replacement, its condition is, if X is a hydrogen, then Y is not a hydrogen;
R
4And R
5Be hydrogen, C independently
1-C
6The C of alkyl or replacement
1-C
6Alkyl, wherein substituent group can be 1-5 halogen, a 1-3 hydroxyl, S (O) m (C
1-C
6Alkyl) or phenyl;
A is
Wherein x is 0 or 1;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, trifluoromethyl, phenyl, replacement
1-C
5Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, C (O) OR
2, C
5-C
7Cycloalkyl ,-N (R
2) (R
2) ,-C (O) N (R
2) (R
2); Perhaps R
7And R
7aCan be independently and R
4And R
5A connection in the group is at end nitrogen-atoms and R
7Or R
7aForm alkylidene bridge between the moieties of group, form 5 yuan or 6 yuan of rings; Perhaps R
7And R
7aCan C of interconnection formation
3Cycloalkyl;
N is 2;
M is 0,1 or 2;
Q is 0,1,2 or 3;
T is 0,1,2 or 3.
Preferred chemical compound comprises chemical compound and pharmaceutically acceptable salt and each diastereomer of CIb in the 3rd specific embodiments:
Formula CIb is wherein:
R
1Be selected from following groups: C
1-C
10Alkyl, aryl (C
1-C
3Alkyl)-, (C
3-C
7Cycloalkyl) (C
1-C
3Alkyl)-, and aryl (C
0-C
1Alkyl)-K-(C
1-C
2Alkyl)-, wherein K is that O, S (O) m, aryl are phenyl, pyridine radicals, naphthyl, indyl, azaindolyl or benzimidazolyl, these aryl can be randomly by 1-2 C
1-C
4Alkyl, a 1-2 halogen, a 1-2 OR
2, S (O) mR
2, or-C (O) OR
2Replace;
R
2Be hydrogen, C
1-C
6Alkyl or C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
5-C
7Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
3aBe hydrogen, or C
1-C
4Alkyl;
X is selected from: hydrogen ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl ,-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl ,-(CH
2)
qS (O) mR
2And-(CH
2)
qS (O) m (CH
2)
tAryl, wherein R
2Group can be randomly by hydroxyl, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab, or tetrazole radical replacement, and aryl is phenyl, naphthyl or pyridine radicals, these groups can be further by 1-2 halogen, a 1-2 OR
2,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
8Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
5-C
7Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl and-(CH
2)
q-K-(CH
2)
t(C
5-C
6Cycloalkyl), wherein K is S (O) m, and wherein alkyl group can be randomly by hydroxyl, carboxyl ,-CONH
2Or carboxylic acid C
1-C
4Arrcostab or 1H-tetrazolium-the 5-base replaces, and aryl is phenyl, naphthyl, pyridine radicals, thiazolyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl or imidazole radicals, and these groups can be randomly by 1-2 halogen, a 1-3 OR
2, 1-2-N (R
2) (R
2), CO (OR
2), a 1-2 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replacement, its condition is if X is a hydrogen, then Y is not a hydrogen;
R
4And R
6Be hydrogen, C independently
1-C
4The C of alkyl or replacement
1-C
3Alkyl, wherein substituent group can be a 1-2 hydroxyl;
Wherein x be 0 or or 1;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, phenyl, replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, perhaps R
7And R
7aCan C of interconnection formation
3Cycloalkyl;
M is 0,1 or 2;
Q is 0,1,2 or 3;
T is 0,1,2 or 3.
Preferred chemical compound comprises those chemical compounds and pharmaceutically acceptable salt and each diastereomer of general formula CIc in this 3rd specific embodiments:
Formula CIc wherein
Its condition is if X is a hydrogen, and then Y can not be a hydrogen;
R
4And R
5Be independently selected from following groups:
-H??????-CH
3?????-CH
2CH
3
Most preferred comprises following compounds and pharmaceutically acceptable salt and each diastereomer (if not explanation in addition) in this 3rd specific embodiments:
In the application's full text; Use has the following abbreviation of following implication: press liquid chromatography NMM N-methylmorpholine NMR nuclear magnetic resonance TFA trifluoroacetic acid THF oxolane TLC thin-layered chromatography TMS tetramethyl monosilane in uncle's BOC fourth oxygen carbonic acyl radical BOP hexafluorophosphoric acid BTA-1-base oxygen three (dimethylamino) Phosphonium CBZ benzyloxy carbonic acyl radical DIBAL-H diisobutylaluminium hydride DMF DMF EDC hydrochloric acid 1-(3-dimethylamino-propyl)-3-ethyl carbodiimides FAB-MS fast atom bombardment-mass spectrum GHRP GHRP HOBT hydroxybenzotriazole LAH lithium aluminium hydride reduction HPLC high pressure liquid chromatography (HPLC) MHz megahertz MPLC
Chemical compound of the present invention all has at least one asymmetric center as marking with an asterisk among the above general structure I.Different because of each substituent character on the molecule, can also there be the other asymmetric center on this molecule.Each such asymmetric center all will produce two kinds of optical isomers, and intentionally that all are such optical isomer, no matter be isolating, pure or partially purified optical isomer, its racemic mixture still is its non-enantiomer mixture, all includes in the scope of the present invention.Under the situation by the asymmetric center of asterisk representative in general formula I, found that active stronger thereby absolute stereo chemistry better isomer is as shown in general formula I I.A kind of equivalents is the R on the structural plan that the C=O group is arranged
1Above being placed on the N-substituent group.The special configuration of this asymmetric center is corresponding to the configuration in the D-aminoacid.In most of the cases, this also is designated as the R-configuration, although this will be because of being used to constitute the R that R-or S-spatial chemistry are arranged
1Value and different.
Formula II
No matter the W group is in R-configuration or the S-configuration if also may reside in.Both can both provide active growth hormone cinogenic agent, although in general the R-configuration has stronger activity.In addition, the W group is with respect to substituent X, Y or R
3Can be cis also can be trans.Under the situation of the asymmetric center that has X group and Y group, as a rule, the R-configuration is all consistent with the useful level of growth hormone secretagogue activity with the S-configuration.In addition, also pointed out the configuration of the many best chemical compounds of the present invention.W, X and Y group are for R
3Substituent group also can be a cis or trans.In some best chemical compounds, also with respect to R
3Substituent group has illustrated cis or trans relation.These all belong to scope of the present invention, and point out these stereochemical orientations in some best chemical compounds.When the carbon atom of being with asterisk in the general formula I has defined and is generally D-form, because of having W, X, Y and R
3Absolute configuration on the carbon atom of group and different can produce diastereomer.These diastereomers at random are called diastereomer d
1, d
2, d
3, d
4Deng, and if be ready that the synthetic or chromatography of their independence separates and can utilize standard method or realize by the method for the invention.Their absolute stereo chemistry can be determined with the X-ray crystallography of crystalline product or crystallization of intermediate, and the available in case of necessity a kind of reagent that contains the asymmetric center of known absolute configuration of these products or intermediate is derived.
The compounds of this invention generally is separated into the form of its pharmaceutically acceptable acid-addition salts, for example, utilizes the deutero-salt of mineral acid and organic acid.The example of this class acid is hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propanoic acid, maleic acid, succinic acid, malonic acid, methanesulfonic acid etc.In addition, some chemical compound that contains acid functional group such as carboxyl also can be separated into the form of its inorganic salt, wherein can be selected from sodium, potassium, lithium, calcium, magnesium etc. to ion, can also be selected from organic base.
The preparation of compound of Formula I of the present invention can be carried out with order or convergence synthetic route.Describe in detail in a sequential manner and introduce synthesizing in following reaction scheme of compound of Formula I preparation.
Here reuse " standard peptide coupling reaction condition " this term, it is meant in a kind of atent solvent such as dichloromethane, in the presence of a kind of catalyst such as HOBT, with a kind of acid activators such as EDC, DCC and BOP, makes a kind of carboxylic acid and a kind of amine coupling.Use blocking group to be beneficial to desired response and to reduce undesirable reaction to greatest extent to amine and carboxylic acid, existing fully record on the document.Remove the blocking group conditions needed that may exist and to consult Greene, T; Wuts, P.G.M.
Protective Groups in Organic Synthesis, John Wiley ﹠amp; Sons, Inc., New York, NY 1991.CBZ and BOC are widely used in this synthetic, and it removes condition is to be familiar with known to the personnel of this gate technique.Removing of CBZ group can realize with technical known many methods; For example, in a kind of proton transfer solvent such as ethanol, in the presence of a kind of noble metal or its oxide such as carried by active carbon are palladic, use the hydrogen catalysis hydrogenation.Should not carry out under the situation of catalytic hydrogenation owing to the existence of other potential active functional group, removing of CBZ group also can be by handling with the acetic acid solution of hydrogen bromide or realizing by the mixture process with TFA and dimethyl sulphide.Removing in a kind of solvent such as dichloromethane or methanol or ethyl acetate with a kind of strong acid such as trifluoroacetic acid or hydrochloric acid or hydrogen chloride gas of BOC blocking group carried out.
Protected amino-acid derivant 1 is commercial under many circumstances to be got, and wherein blocking group L is such as BOC or CBZ group, and other protected amino-acid derivant 1 can prepare (Williams, R.M. with literature method
Synthesis of Optically Activeα-Amino
Acids, Pergamon Press:Oxford, 1989).The piperidines of general formula 2, pyrrolidine and hexahydro-1 H-azepines have and manyly are that commerce can get or are known on the document, other can be according to the literature method preparation of describing for known compound, the some of them method will here be described.React and the needed technical ability of purification of institute's reaction of formation product is that to be familiar with the personnel of this gate technique known.Purification step comprises crystallization and positive or reverse-phase chromatography.
The intermediate of general formula 3 can synthesize as described in the scheme 1.The amine of general formula 2 (if not known compound, then its preparation is being described after a while) carries out under standard peptide coupling condition easily with the coupling of the protected amino-acid (wherein L is a suitable protecting group) of general formula 1.
3 change into intermediate 4 is undertaken by utilizing the standard method opinion to remove blocking group L (CBZ, BOC etc.) can be in scheme 2 illustrated.
(A is connected with phosphinylidyne by a carbon atom intermediate of general formula 5 in the formula, thereby A is-(CH
2) x-C (R
7) (R
7a)-(CH
2)
y-) can shown in scheme 3, under standard peptide coupling reaction condition, allow the intermediate of general formula 4 and the aminoacid coupling of general formula 5 prepare.The same with amino acid/11, aminoacid 5 or commercial getting, or can synthesize.And if R
4Or R
5Be a hydrogen, then protected amino-acid 6 also can be used for this coupling reaction, and wherein L is a blocking group as defined above.Remove the L in 7 and provide I (R wherein
4=H) can carry out under the known technically condition.
The chemical compound of general formula I (R in the formula
4And/or R
5Be a hydrogen) can be shown in scheme 4, further making has the noval chemical compound of replacement I (best side chain R to be arranged on the amino
4=CH
2-CH (OH)-CH
2X, X=H or OH in the formula).Aldehyde is to carrying out under the known technically condition of the standard reductive alkylation of I; For example, in the presence of platinum, palladium or Raney nickel, use the hydrogen catalysis hydrogenation, or in a kind of proton transfer solvent, use chemical reducing agent such as sodium cyanoborohydride catalytic hydrogenation in the presence of the acid at catalytic amount.In addition, similarly conversion also can realize by the epoxide ring-opening reaction.
Scheme 5
Its A is Z-(CH
2) x-C (R
7) (R
7a)-(CH
2)
y-and Z be N-R
6Or the compound of Formula I of O, can be shown in scheme 5, making its X is that 4 of a good leaving group such as Cl, Br, I or imidazoles prepares with reagent 8 reactions.In addition, 4 can be at a kind of atent solvent as 1, and with a kind of isocyanate reaction of general formula 9, it is the compound of Formula I of NH that its Z is provided in the 2-dichloroethanes.
Compound of Formula I of the present invention also can prepare in a kind of convergence mode as described in reaction scheme 6,7 and 8.
Amino acid derivativges 10 is commercial under many circumstances gets for the protection of the carboxylic acid of its M=methyl ester, ethyl ester or benzyl ester.The aminoacid of other ester protection can prepare with the classical way that the person skilled in the art was familiar with.Aminoacid and a kind of alcohol reaction and azeotropic dehydration under some existence that are included in a kind of sour example hydrochloric acid or p-methyl benzenesulfonic acid are arranged in these methods.Other method is included under the existence of a kind of catalyst such as DMAP a kind of protected amino-acid and a kind of diazoparaffins or with a kind of pure and mild a kind of acid activators such as EDC, DCC reaction and remove blocking group L.
The intermediate of general formula 11 or 11a can prepare by the aminoacid coupling of amino-acid ester 10 with general formula 6 or 7 shown in scheme 6.When 11 or 11a in when having a urea key, introduce it is can be in scheme 5 illustrated.
Ester 11 or 11a change into intermediate acid 12 or 12a, can realize with technical known many methods described in scheme 7; For example, methyl ester and ethyl ester can be used the Lithium hydrate hydrolysis in a kind of proton transfer solvent such as methanol aqueous solution.In addition, removing of benzyl group can be realized with many reproducibility methods.Comprising in a kind of proton transfer solvent such as methanol in the presence of palladium catalyst hydrogenation.Allyl ester can comprise in ethyl acetate and the dichloromethane at various solvents, in the presence of 2 ethyl hexanoic acid, makes it fracture with four (triphenyl phasphine) palladium catalyst and (sees
J.Org.Chem., 42,587 (1982)).
Scheme 8
Then, acid 12 or 12a make I or chemical compound 7 can be described in scheme 8.The coupling of the acid of the piperidines of general formula 2, pyrrolidine or hexahydro-1 H-azepines and general formula 12 or 12a (L is a suitable blocking group in the formula) is to carry out easily under standard peptide coupling reaction condition.7 change into I realizes by removing blocking group L.Work as R
4And/or R
5When being H, there is the alkyl of replacement randomly to add on the nitrogen-atoms can be described in scheme 4.
Piperidines, pyrrolidine or hexahydro-1 H-azepines or commercial getting that 2-replaces, or can prepare with literature method.Its preparation method illustrates for example at this, but whole anything but.
According to S.Murahashi and T.Shiota (
Tetrahedron Lett.,
28, 6469-6472 (1987)) and the scheme that proposes, cyclammonium class such as piperidines, pyrrolidine or hexahydro-1 H-azepines are handled the Alpha-hydroxy amino nitrile that provides general formula A14, (Murahashi, S.-I. when the latter reduces with Blausure (German) then with catalytic oxidation of hydrogen peroxide; Kodera, Y.,
Tetrahedron Letters,
26, 4633-4636, (1985)) and provide the alpha-aminonitriles of general formula A2a.At X and Y is not that hydrogen and/or n are not that orientation isomer (regio-isomers) and diastereomer may produce under 2 the situation, but they can separate with chromatography.The hydrolysis of this amino nitrile under acidity or alkali condition produces aminoacid.In addition, this hydroxyl amino nitrile also can first hydrolysis, then with the reduction of palladium catalytic hydrogenation method, provides the aminoacid of general formula A15.Zhi Bei aminoacid and derivant thereof are racemic according to the method.
In addition, nitrile A2a also can look like document (Goti and Romani,
Tetrahedron Letters,
35, 6567-6570 (1994)) described in make compd A 13 be oxidized to imines like that to react with cyanide then and prepare.W also can with butyl lithium make compd A 13 direct alkylations carrying out the subsequently electrophilic reagent addition of BOC protection be so-called Beak alkylation process (Beak and Lee,
J.Org.Chem.,
55, 2578-2580 (1990)) introduce.The asymmetric introduction of W also can realize with chiral catalyst (Kerrick and Beak,
J.Am. Chem.Soc.,
113,9708-9710 (1991)).
Carboxylic acid functional on the general formula A15 chemical compound 2-position can be according to (the The Practice of PeptideSynthesis of the known commonsense method of a lot of record and this gate technique skilled person on the document; M.Bodanszky and A.Bodanszky; Springer-Verlag; 1984) change into ester, amide, nitrile, acyl group sulfonamide and the defined residue of W, provide the chemical compound of general formula 2.L is a due care group, as BOC, CBZ etc.This carboxylic acid also can change into its next higher homologue with the Arndt-Eistert reaction, or changes into derivant such as the amide or the ester of this homologue acid.In addition, this ester can exist according to C.J.Kowalski and R.E.Reddy
J.Org.Chem.,
57, the anionic scheme of describing among the 7194-7208 (1992) of use alkynes alcoholates (ynolate) is directly carried out homologization (homologate).Formed acid and/or ester can change into next higher homologue again, and the rest may be inferred.
Option A 11
Illustrated in the option A 11 is the universal method of a kind of Y of introduction, wherein X be a kind of electron withdraw group as-CN ,-CO
2R
8, R in the formula
8Be alkyl, aryl and alkyl (C
1-C
4) aryl, these or known compound perhaps can prepare those used methods preparations with said method or with being similar to known compound.The introduction that Y replaces can be achieved like this: in a kind of atent solvent such as THF, temperature-100 ℃~room temperature, allow chemical compound and a kind of highly basic of general formula A18 react earlier, add alkylating reagent such as alkyl halide, aryl alkyl halogen, carboxylic acid halides and haloformates then as two (trimethyl silyl) ammonification potassium, diisopropyl lithamide.The sulfur derivatives that sulfur is directly connected on the alkyl or aryl can be by being prepared with the disulphide reaction similarly.The halogenide that uses in these reactions or commercial available, or compound known on the document perhaps can prepare those used method preparations with being similar to known compound.Blocking group in Formula B 19 chemical compounds can remove with ordinary chemical method, provides the chemical compound of general formula 2.
Option A 12
In order to prepare the high proline of cis (homotype proline) derivant, can use the described step of people (Shuman, R.T. such as Shuman; Ornstein, P.L.:Paschal, J.W.; Gesellchen, P.D., J.
Org.Chem.,
55, 738-741 (1990)) and (option A 12).General formula A20 substituted pyridines (wherein many is commercial maybe can preparing with literature method of getting) is arranged is by changing into its corresponding N-oxide with hydroperoxidation.This pyridine N-oxides and trimethyl silyl cyanogen and dimethylcarbamyl chloride reaction provide the 2-nitrile of general formula A21.If produce the orientation isomer certainly owing to the existence of 3-replacement, then they can separate with chromatography easily.This nitrile is hydrolyzed into acid and uses the platinum oxide catalytic hydrogenation subsequently under acidity or alkali condition, provide piperidine carboxylic acid.This carboxylic acid functionalized sees above and partly as described in the option A 10.
The aminoacid that these synthetic schemes produce is racemic.Yet, in all sorts of ways tear open the step of analysing the RS-a-amino acid be known on the document (Toone, E.J. and Jones, J.B.,
Can.J.Chem., 65,2722 (1987); Okamoto, S.; Hijikato, A.,
Biochem.Biophys.Res.Commun.,
101, 440 (1981); Greenstein, J.P.; Winitz, M.,
Chemistry of the Amino AcidsWiley:NewYork,
1961, Vol.1,715-760).Therefore, isolating R-and S-isomer can be discussed preparation in this way.In addition, racemic piperidines, pyrrolidine and hexahydro-1 H-azepines derivant can directly change into growth hormone cinogenic agent or its intermediate, and the non-enantiomer mixture that is generated can separate the generation enantiopure compound in the suitable stage with chromatography.
In addition, can carry out asymmetric synthesis, with the pure piperidines of synthesizing optical, pyrrolidine and hexahydro-1 H-azepines derivant.For example, optically active piperidines-2-carboxylic acid derivates A15a and A15b can with people such as Bailey (
J.Chem.Soc.Perkin Trans I, 1337-1340 (1991)) and described azepine-Diels-Alder prepared in reaction.In the reaction between chiral imines A23 and the diene A24 in the presence of TFA (1 equivalent) and the water (catalytic amount), provide addition product A25 and A26 with good cis-selectivity.These two kinds of diastereomers can separate, and each can hydrogenation so that two key reduction and remove chiral auxiliary.Opinion can realize all four kinds of possible isomers in this way.Here Shuo Ming (option A 13) is the preparation that two kinds of S-configuration isomer A15a and A15b is arranged adjoining on the chiral centre of COOH.These supercentral two kinds of R-isomers can be prepared similarly with compd A 26.
The existing play-by-play in many research papers of synthesizing that substituted piperidine is arranged of general formula 2 (n=2).For example, people such as S.M.N.Efange (
J.Med.Chem.,
36, 1278-1283 (1993)) and people such as M.S.Berridge (
J.Med.Chem.,
36, 1284-1290 (1993)) and the pyridine intermediate B13 that used 4-to replace synthesizes the 4-substituted-tetrahydro piperidines of Formula B 14 (L=methyl) describing in option b 9.Removing of L can be carried out with many methods that this gate technique skilled person is familiar with on the piperidines of Formula B 14, exists comprising people such as H.Ong
J.Med.Chem., 23,981-986People such as Bromine cyanide. scheme that describes in detail (1983) and R.Olofson exist
J.Org.Chem., 23, 2795 (1984) the middle ACE-Cl methods of describing.For the intermediate of Formula B 14 (L=Bn in the formula), when removing with hydrogenation of olefins, benzyl group carry out in a kind of proton transfer solvent such as methanol, to use platinum or palladium catalyst to realize.In addition, B13 can directly be transformed into the piperidines of Formula B 15 (L=H) by reducing with platinum oxide in a kind of proton transfer solvent of the acid that catalytic amount arranged such as methanol.
Option b 10
Also can use the chemical compound of the synthetic general formula 2 of other method as shown in option b 10.For example, the enol triflates and the Formula B 17 (Xa=B (OH) of Formula B 16 (L=blocking group, X and Y are defined in the general formula I in the formula)
3) aryl boric acid or Formula B 17 (Xa=SnMe
3) aryl or the cross coupling of phenyl or naphthyl tin reagent, can exist as W.J.Scott and J.E.McMurry
Acc.Chem.
Res.,
21,Describe in detail in 47 (1988) the survey article like that, realize with palladium (II) or palladium (O) catalyst, provide the tetrahydrochysene piperidines B18 (L=blocking group) in their example.There are various methods to can be used for the enol triflate intermediate and the general formula 17 (X=B (OH) of synthetic general formula 16
3SnMe
3) phenyl or naphthyl boric acid and phenyl or naphthyl tin reagent, and all be that this gate technique skilled person is familiar with.Remove blocking group L and just provide, for example, the piperidines of Formula B 19 (L=H).The B18 hydrogenation removes blocking group L subsequently and also provides saturated derivatives B20.In addition, B19 can also be in a kind of proton transfer solvent such as methanol, makes hydrogenation of olefins and change into the chemical compound of Formula B 20 in the presence of platinum or palladium catalyst.
There is the synthetic method of substituted pyrrolidin, piperidines and hexahydro-1 H-azepines also to include the addition that replaces and/or do not have oxo-piperidine, oxo-pyrrolidine or the oxo hexahydro-1 H-azepines of substituted alkyl, cycloalkyl, phenyl or naphthyl Grignard reagent or lithium reagent mutual-through type B21 (L=benzyl, methyl etc.), provides the chemical compound of Formula B 22 (L=benzyl, methyl etc.).The dehydration of the hydroxyl of B22 (L=benzyl, methyl etc.) produces B18 (L=benzyl, methyl etc.), can by with strong acid treatment it or undertaken by reacting from the elimination of the deutero-corresponding methylsulfonyl thing of B22 (L=benzyl, methyl etc.).Compound B-11 8 can change into B19 or B20 as previously discussed like that.
3 of Formula B 21 (X is an electron withdraw group such as ester, ketone, nitrile etc. in the formula), 4-3-disubstituted piperidine, pyrrolidine and hexahydro-1 H-azepines can be with the further alkylation of the method that this gate technique skilled person is familiar with, hydroxylating, halogenations.Again, the deprotection of blocking group L can carry out with the method that this gate technique skilled person is familiar with.
Specifically, the ortho position substituted phenylpiperidines of Formula B 22a (X, Y=H in the formula) can from Phenylpiperidine intermediate B 23 preparation (see people such as S.M.N.Efange,
J.Med.
Chem.,
26,1278 (1993)).
Option b 13
As shown in option b 13, benzylalcohol can be oxidized to aldehyde B24 with the variety of processes that this gate technique skilled person is familiar with.Method commonly used is the manganese dioxide in a kind of atent solvent such as chloroform, or the Swern scheme.Can elaborate various functional groups from B24 now.For example, with the acetic acid triethylphosphine Emmons reaction taking place provides alpha, beta-unsaturated esters B25 in the presence of alkali.In a kind of alcoholic solvent, pyridine unit and thiazolinyl group are reduced simultaneously, the piperidines of Formula B 26 (X, Y=H in the formula) is provided with platinum or palladium catalyst.Piperidines B26 can be derivatized to the chemical compound that has ester and acid in the general formula I (X and Y=H in the formula) with the chemical reaction that describes in detail in the scheme 1~8.In addition, by with Corey scheme (NaCN, acetic acid, MnO
2, in methanol) and make aldehyde radical be oxidized to ester, in a kind of proton transfer solvent such as methanol, make pyridine be reduced into piperidines subsequently with platinum or palladium catalyst, also can directly be transformed into methyl ester B27 (X, Y=H in the formula) to B24.Piperidines B27 can utilize the chemical process that describes in detail in the scheme 1~8 to elaborate the chemical compound of general formula I.The piperidines unit of B27 can be protected with various blocking group L that this gate technique skilled person is familiar with, and ester units can provide sour B28 (X, Y=H in the formula) with the method hydrolysis of many records on the document.Acid intermediate B 28 can be used for preparing the chemical compound that those have various highly functional piperidines, can be transformed into compound of Formula I.
The highly functional Phenylpiperidine of Formula B 22 (X, Y=H in the formula) can utilize the synthetic method preparation of following detailed description.
As shown in option b 14, piperidines B26 also can serve as a kind of key intermediate, is used for the various piperidines of synthetic Formula B 22a, R in the formula
10Can be alkyl and aryl amide, alkyl and aryl-acyl sulfonamide, alkyl and aryl urea, alkyl and aryl-carbamate etc.The piperidines nitrogen of B26 can be protected with blocking group L (group commonly used comprises BOC, CBZ, FMOC) with the method for a lot of record on the document, and ester units can provide B29 with sodium hydroxide or potassium hydrolysis in water or pure medium now.The peptide type coupling of B29 and firsts and seconds aliphatic amine, arylamine, due care aminoacid, alkyl or aryl sulfonamide provides the amide (X, Y=H in the formula) of Formula B 30, removes blocking group L subsequently.In addition, sour B29 can be with phosphinylidyne diimidazole activation, subsequently in a kind of atent solvent such as oxolane or dimethyl formamide with firsts and seconds aliphatic amine, arylamine; due care aminoacid, alkyl or aryl sulfuryl amine reaction provide the amide of Formula B 30, X, Y=H in the formula; L on nitrogen, R
2And R
6It can be described any group in the scope of the invention.The urea of Formula B 30a (X, Y=H in the formula, L on nitrogen, R
2And R
6Can be described any group in the scope of the invention) can be synthetic from B29, its way is to carry out Curtius to reset reuse general formula HNR
2R
2Or HNR
2R
6Amine capture isocyanates intermediate.Blocking group L can remove, and the chemical process of introducing in the reuse scheme 1~8 is elaborated the chemical compound of general formula I.
Acid intermediate B 29 can be served as a kind of key intermediate, is used for the band heterocyclic compound (formula X, Y=H) of synthetic Formula B 32.As shown in option b 15, acid B29 can change into the nitrile (X, Y=H in the formula) of Formula B 31 in proper order with one three step, comprising in the presence of a kind of alkali such as triethylamine, making this acid activation with ethyl chloroformate, add ammonia producing the one-level amide, and in pyridine, make this dehydration of amide become a kind of nitrile with inferior phosphoryl chloride phosphorus oxychloride.Now, nitrile intermediate B 31 can be by making it to heat the piperidines that changes into Formula B 32 with the Azide trimethyl tin X, Y=H and R in the formula in a kind of atent solvent such as toluene or dimethylbenzene
11It is a kind of 1H-tetrazolium.Blocking group L can remove, and the chemical process that describes in detail in the reuse scheme 1~8 is elaborated the chemical compound of general formula I.
Having other heterocyclic Formula B 32 piperidines prepares from intermediate B31 also can be shown in option b 16.Nitrile B31 handles with anhydrous hydrochloric acid in dried ethanol, provides the imido ether of Formula B 33.This intermediate is heated in formylhydrazine and B33 addition subsequently in a kind of atent solvent such as toluene, piperidines (X, Y=H in the formula, the R of Formula B 32 is provided
11Be 1,2, the 4-triazole).In addition, the methoxycarbonyl hydrazine also can with imido ether B33 addition and cyclisation, B32 is provided (X, Y=H and R in the formula
11Be a kind of Triazolinones).B33 under high pressure reacts with dihydroxy acetone in methanol ammonia, provides B32 (X, Y=H and R in the formula
11Be a kind of hydroxy methylimidazole).Blocking group can remove with the method that this gate technique skilled person is familiar with, and utilizes the chemical process that describes in detail in the scheme 1~8 to elaborate the chemical compound of general formula I again.
In addition, acid, acyl chlorides, nitrile and imido ether also can serve as key intermediate, and being used to prepare many other has alkyl, phenyl, hydroxyl and the amino heterocycle that replaces.Wherein a lot of methods can be consulted A.R.Katrizky,
Handbook of Heterocyclic Chemistry,Pergamon Press, 1985, New York, NY, and can be used to synthetic various band heterocyclic compounds.
Have one and other suitable synthetic route of dibasic general formula I I (n=1 or 2) pyrrolidine, piperidines and hexahydro-1 H-azepines be known on the document.For example, J.J.Plati and W.Wenner (
J.Org.Chem., 14,543 (1949)) and verified, ketoamine intermediate B 34 can be elaborated B35 (n=1,2,3) under 3-hydroxybutyraldehyde condensation condition.The B35 dehydroxylation can be realized in many ways, is included in the catalytic hydrogenation method that utilizes palladium catalyst in a kind of proton transfer solvent such as the methanol.The removing in all sorts of ways of the last L of B36 carried out, comprising the described ACE-Cl method of people such as R.Olofson (
J.Org.
Chem.,
43, 2795 (1984)).
3 of general formula 2 (n=2), the synthetic of 4-3-disubstituted piperidine can prepare easily with literature method.Below explanation is one of these universal methods.The cis 3 that G.T.Borrett is verified carries out from the commercial ethyl nicotinate that gets and Grignard reagent R3 MgBr (R3 defines in the general formula I the formula), synthetic (United States Patent (USP) 4,861,893) of 4-3-disubstituted piperidine B39.The ester functional group of B38 can pass through the further modification of general chemistry method, so that the defined X of other functional group in the scope of the invention to be provided.Here illustrational just some and all can be used to prepare the method for the X of functional group anything but.For example, the ester of B38 can hydrolysis to provide corresponding carboxylic acid B39 (X=CO
2H); B39 can change into amide (X=CONR by simple peptide type coupling reaction subsequently
2R
2), by Curtius reset (Smith,
Org.React.,
3, 337 (1946)) catch the isocyanates intermediate with amine or alcohol then and change into urea or carbamate (X=NC (O) NR
2R
2, NC (O) OR
2), or change into a kind of methylol unit (X=CH by borane reduction
2OR
2).Acid B39 also can change into a kind of nitrile, elaborates heterocyclic compound (X=tetrazole radical, triazolyl, triazoline base etc.) with the step described in option b 15 and the B16 then.Carboxylic acid B39 (X=CO
2H) also can change into its more high-grade homologue B39 (X=CH with the Arndt-Eistert reaction
2CO
2H), reuse method already described above is further derived.
Option b 19
Cis 3,4-disubstituted piperidine B38 can as shown in the option b 19 in a kind of proton transfer solvent with the alkali of catalytic amount such as Sodium ethylate treatments B 38 and change into trans 3,4-disubstituted piperidine B40.Again, the further modification of method that the ester functional group of B40 can be familiar with this gate technique skilled person is comprising the step described in the option b 18.Can remove by the general chemistry method by the blocking group L on the chemical compound of B39 and B41, and utilize chemical method described above to be refined into the chemical compound of general formula I.
As cis 3 described in the option b 20, Formula B 43, the 4-3-disubstituted piperidine can prepare B42 and ethyl nicotinate addition by the step with G.T.Borrett (United States Patent (USP) 4,861,893).The acetal protecting group can remove with many methods that this gate technique skilled person is familiar with.The aldehyde B44 that is generated serves as a kind of key intermediate, is used for 3 of synthetic highly functionalization, the 4-3-disubstituted piperidine.The corresponding carboxylic acid B45 of the oxidable one-tenth of aldehyde B44 further elaborates various functional groups, then as amide, urea, carbamate, acyl group sulfonamide etc.Some examples of these conversions connect discussion with option b 14.
Option b 21
Compd B 44 also can change into alpha, beta-unsaturated esters or nitrile with the Emmons reaction.Beta-unsaturated esters that is generated or nitrile can be used the palladium or the platinum hydrogenation of catalytic amount under nitrogen atmosphere.Dibasic acid esters B45 (X=CO as shown in option b 21
2Et, E=CO
2Et) can optionally be hydrolyzed into corresponding sour B45 (X=CO
2Et, E=CO
2H), the latter can further elaborate various functional groups in many ways.Formula B 31 (X=CO
2Et, chemical compound E=CN) can become the chemical compound (X=CO of Formula B 32 with Azide tin trimethyl thermal conversion in toluene by making B31
2Et, Y=H, R
11=1H-tetrazolium).In addition, nitrile intermediate B 31 (for example, its X=CO
2Et E=CN) also can serve as a kind of synthetic precursor, is used for synthetic B32 (X=CO
2Et) band heterocyclic compound.More than Shuo Ming synthetic method much can be consulted A.R.Katrizky,
Handbook of Heterocyclic Chemistry, Pergamon Press, 1985, New York, NY, and interrelate with option b 16 and to discuss.
With 3 of these synthetic schemes generations, 4-two substituted compounds 2 are racemic.A replacement that produces with these synthetic schemes and disubstituted pyrrolidines and hexahydro-1 H-azepines 2 also are racemic.The chiral intermediate of general formula 2 can obtain in many ways, analyses comprising tearing open with the classics of racemate.For example, tear open and analyse and to realize by the acid of racemic amines and optical activity as D-and L-tartaric acid formation diastereoisomeric salt.The mensuration of absolute stereo chemistry can be carried out in many ways, comprising the X-radiocrystallgraphy of suitable crystalline derivatives such as D-or L-tartrate.In addition, also can carry out asymmetric synthesis and come the synthesizing optical pure compound.
And then, the racemic intermediate of general formula 2 can be derived with chiral reagent, its product can separate with chromatography, and the chipal compounds of general formula 2 can be regenerated from them with Hydrolyze method, or as previous said, the racemic intermediate of general formula 2 can directly change into growth hormone cinogenic agent, and the non-enantiomer mixture that is generated can separate and the chemical compound of generation enantiomer-pure with chromatography.
Scheme C9
3 one substituted piperidines of general formula C13 can by pyridine derivate or its salt a kind of suitable organic solvent such as water, acetic acid, alcohol as ethanol or its mixture in, in the presence of a kind of noble metal catalyst such as platinum or its oxide (on a kind of carrier such as active carbon), easily under room temperature and the atmospheric pressure or under high temperature and high pressure, hydrogenating reduction prepares.3 monobasic piperidines also can prepare by the X or the modification of Y residue of existing 3 one substituted piperidines.
3 monobasic pyrrolidines are commercial getting, or can prepare with literature method easily.Shown in the scheme C9A is an example for preparing these chemical compounds by pyrrolidine-3-carboxylate.The commercial chemical compound 1-benzyl that gets-4-oxo-3-pyrrolidine carboxylic acid methyl ester borane reduction (
J.Chem.Soc.,
24,1618-1619).Catalytic hydrogenolysis removes benzyl group, carries out ester exchange in the presence of acid subsequently in a kind of suitable pure medium such as ethanol, has provided Compound C 13b.This ester degree of functionality can become defined other group of X by the further modification of ordinary chemical method.3-substituted pyrrolidin also can prepare by the catalytic hydrogenation of 3-substituted azole.
Scheme C9B
Hexahydro-1 H-azepines is commercial getting, and also can prepare with literature method.Hexahydro-1 H-azepines-3-carboxylic acid (Krogsgaard-Larsen, people such as P.,
Acta.Chem.Scand.,
B32, 327 (1978)) and be esterification in the presence of the acid in a kind of alcoholic solvent.The ester degree of functionality can become other group in the X range of definition by the further modification of ordinary chemical method.
What illustrate among the scheme C10 is a kind of universal method for preparing 3-disubstituted piperidine, pyrrolidine and hexahydro-1 H-azepines.The chemical compound of general formula C13 (in the formula X be an electron withdraw group as-CN ,-CO
2R
8, R wherein
8Be alkyl, aryl and (C
1-C
4Alkyl) is known compound aryl), maybe can prepares those used method preparations with being similar to these known compounds.The secondary amine of general formula C13 chemical compound can adopt ordinary skill earlier with a blocking group L such as BOC and CBZ protection.The introduction that Y replaces can be by allowing chemical compound and a kind of highly basic of general formula C14 react as two (trimethyl silyl) lithamide, diisopropyl lithamide earlier; in a kind of atent solvent such as THF, add alkylation or acylating reagent such as alkyl halide, aryl alkyl halogen, carboxylic acid halides and haloformate in the temperature of-100 ℃~room temperature and realize subsequently.The sulfur derivatives that sulfur is directly connected on an alkyl or the aryl can prepare by reacting with disulphide similarly.The halogenide or commercial the getting of using in these reactions, or be compound known on the document, or can prepare those used method preparations with being similar to known compound.Blocking group L in the general formula C15 chemical compound can remove with the general chemistry method, provides the chemical compound of general formula 2.
Scheme C11
Other preparation methoies of general formula 2 chemical compounds comprise ring itself structure (Jacoby, people such as R.L.,
J.Med.Chem.,
17,453-455 (1974)).General formula C16 cyan-acetic ester is commercial maybe can preparing with literature method of getting, and makes it alkylation with alkyl dihalide such as 1-bromo-2-ethyl chloride or 1-bromo-3-chloropropane and has produced chloride C17.Nitrile C17 borane reduction, or carry out hydrogenating reduction as catalyst with Raney Ni, having provided corresponding primary amine, the latter provides the chemical compound of general formula 2a when refluxing in ethanol.
Scheme C12
In addition, the cyan-acetic ester of general formula C16 can also be with the alkylation of a kind of ethoxy phosphinylidyne alkyl bromide, or with the ethyl acrylate reaction, and provide the chemical compound of general formula C18.Nitrile C18 borane reduction, or carry out hydrogenating reduction as catalyst with Raney Ni, having provided corresponding primary amine, the latter provides lactams C19 when refluxing in ethanol.Lactams C19 provides the chemical compound of general formula C2a with borane reduction.
Scheme C13
In addition, the malonate of general formula C20 can be used the alkylation of cyano group alkyl bromide, also can with acrylonitrile reactor, generate the chemical compound of general formula C21.Nitrile C21 borane reduction, or carry out hydrogenating reduction as catalyst with Raney Ni, having provided corresponding primary amine, the latter provides lactams C22 when refluxing in ethanol.Lactams C22 provides the chemical compound of general formula C2a with borane reduction.
X, Y degree of functionality in the chemical compound of general structural formula C15 can further be elaborated the group that can't obtain by direct alkylation.For example, in Compound C 15, work as X=CO
2During Et, this ester (supposing that this is the unique ester group in this molecule) can be saponified into carboxylic acid, and the latter can also further be derivatized to amide or other ester.This carboxylic acid can change into its high one-level homologue, or reacts the derivant that changes into this homologue acid, for example amide or ester with Arndt-Eistert.In addition, this ester can also pass through C.J.Kowalsk; Exist with R.E.Reddy
J.Org.Chem.,
57, the anionic scheme of describing among the 7194-7208 (1992) of use alkynes alcoholates is directly carried out homologization.Acid that is generated and/or ester can change into high one-level homologue again, and the rest may be inferred.Blocking group L can remove by the general chemistry method.
Ester among the C15a can be in a kind of suitable solvents such as THF or ether with a kind of Reducing agent such as DIBAL-H and easily-100 ℃~0 ℃ temperature, be reduced into a kind of pure C18.This alcohol can be in a kind of suitable solvents such as dichloromethane, and with a kind of carboxylic acid halides or anhydride, in the presence of a kind of alkali such as triethylamine (TEA), acidylate becomes Compound C 19.Hydroxyl among the C18 also can change into a good leaving group such as mesyl thing, a kind of nucleopilic reagent of reuse such as cyanide, a kind of mercaptan or the displacement of a kind of azide.Azide in the general formula C20 chemical compound is reduced into amine C21, can by in the presence of a kind of noble metal such as palladium or its oxide or Raney nickel in a kind of proton transfer solvent such as ethanol hydrogenation realize.Nitrile can reduce and provide homologue amine.The amine of general formula C21 can further be elaborated the defined amide of X, urea, sulfonamide by the general chemistry method.Blocking group L can remove by the general chemistry method.
Scheme C16
Under oxygen was directly connected to situation on the ring, a kind of method easily related to a kind of commercial ketone generation additive reaction that gets of a kind of activated form of alkyl, aryl, alkaryl such as lithium reagent, Grignard reagent etc. and general formula C28.The hydroxyl that is generated is further derived by acidylate, sulfonylation, alkylation etc., can provide Y or the defined chemical compound of X via the general chemistry method.Removing of benzyl protecting group can be carried out under typical conditions, provides the chemical compound of general formula C2b.Shown in the scheme C16 is a general example of acidylate.
Under a nitrogen substituted radical was directly connected to situation on the ring, a kind of method easily was to use Curtius to reset to sour C23, provides isocyanates C31.The addition of amine or alcohol provides urea or carbamate respectively, and the latter can deprotection removes L and provides the special case of general formula C2 chemical compound.The isocyanates hydrolysis changes into amine and provides Compound C 32.The amine groups that is generated is further derived to provide the defined chemical compound of Y or X by acidylate, sulfonylation, alkylation etc., all can be undertaken by the general chemistry method.Removing of blocking group L can be carried out under usual conditions, provides the chemical compound of general formula C2c.Shown in the scheme C17 is a general example of acidylate.
For the chemical compound that is not easy to obtain, can carry out the modification that can easily obtain chemical compound of general formula C15, to realize desirable replacement by the general chemistry method by the direct alkylation as shown in scheme C10.For example, Y is that the chemical compound of acrinyl can be that the demethylation of the corresponding chemical compound of methoxybenzyl prepares by its Y.Similarly, Y is that the chemical compound of aminobenzyl can be the also original preparation of the corresponding chemical compound of nitrobenzyl by its Y.Shown in the scheme C18 is a kind of example that utilizes nitrile as the program of the starting point that the different compound that replace are arranged.Blocking group L removes the chemical compound that provides general formula C2 described in the scheme C10.
In this way Zhi Bei general formula C2 chemical compound when X and Y be not racemic simultaneously.Tearing open of two kinds of enantiomer analysed and can be realized easily with classical crystallization process, promptly uses a kind of chiral acid such as L-or D-tartaric acid, (+) or (-)-10-camphorsulfonic acid, crystallization in a kind of suitable solvents such as acetone, water, alcohol, ether, acetas or its mixture.In addition, racemic amines C2 also can with a kind of chiral auxiliary as (R) or (S)-reaction of O-acetyl mandelic acid, separate two kinds of diastereomers with chromatography subsequently, the reuse Hydrolyze method removes chiral auxiliary.In addition, can also utilize asymmetric alkylation, can remove chiral auxiliary to the X position or replace L to come the synthesis of optically active intermediate, separate diastereomer with chromatography subsequently by introducing one.
In molecule, have under the situation of sulfide existence, can be with oxidant such as sodium metaperiodate, metachloroperbenzoic acid or Oxone in a kind of solvent such as dichloromethane, alcohol or water or its mixture
It is oxidized to a kind of sulfoxide or is oxidized to a kind of sulfone.
Chemical compound of the present invention also can have from general formula D 46 various and replaces natural and the alpha-non-natural amino acid preparation.Wherein the preparation of a lot of acid can be consulted U.S. Patent No. 5,206,237.The preparation that is these intermediate of racemic form is the (Williams that realizes with the classical way that this gate technique skilled person is familiar with, R.M., " Synthesis of OpticallyActive α-Amino Acids ", Pergamon Press:Oxford, 1989; Vol.7).There are some kinds of methods to can be used to tear open and analyse (DL)-aminoacid.One of common method
Be to tear the intermediate of analysing amino or carboxy protective open by making from optically active acid or the deutero-salt crystallization of amine.In addition, the amino of carboxy protective intermediate also can utilize chemical method described above and optically active sour coupling is arranged.Each diastereomer makes the chiral amides hydrolysis after separating with chromatographic technique or with crystallization process, can provide and tear the aminoacid of analysing open.Similarly, the intermediate of amido protecting also can change into the mixture of non-mapping ester of chirality and amide.This mixture separates with the above method and makes each diastereomer hydrolysis, and (D) and (L) aminoacid are provided.At last, (DL)-enzymatic of amino acid whose N-acetyl derivative tear open the method for analysing by Whitesides and colleague thereof at J.Am.Chem.Soc., 1989,111, report among the 6354-6364.
When wishing these intermediate of the pure form of synthesizing optical, the method for having set up comprises: the electric amination of asymmetric parent of (1) chirality enolate (
J.Am.Chem.Soc.1986,
108, 6394-6395,6395-6397 and 6397-6399), the asymmetric nucleophilic amination of (2) optical activity phosphinylidyne derivant (
J.Am.Chem.Soc.1992,
114, 1906;
Tetrahedron Lett.1987,
28, 32).(3) the cis-selectivity alkylation of chirality glycine enolate synthetic fibers (
J.Am.Chem.Soc.1991,
113, 9276;
J.Org.Chem.1989,
54, 3916), the cis-selectivity nucleophilic addition of the electric glycinate synthetic fibers of (4) chirality parent (
J.Am.Chem.Soc.1986,
108,1103), asymmetric hydrogenation (" AsymmetricSynthesis, Chiral Catalysis:Morrison, J.D., the Ed of (5) prochirality dehydroamino acid derivant; AcademicPress:Orlando, FL, 1985; Vol 5) and (6) enzyme process synthetic (Angew, Chem.Int.Ed.Engl.1978,
17,176).
For example, the enolate D47 of Er Ben Ji oxazinone (
J.Am.Chem.Soc.1991,
113,9276) carry out smoothly with the cinnamyl bromide alkylation in the presence of two (trimethyl silyl) ammonification sodium, provide D48, the reuse trifluoroacetic acid removes uncle's N-fourth oxygen phosphinylidyne group and uses PdCl
2Catalyst hydrogenation changes into desirable (D)-2-amino-5-phenyl valeric acid D49 (scheme D14).
The intermediate of general formula D 46, i.e. O-benzyl-(D)-serine derivative D51, be from benzyl halide that suitable replacement is arranged and N-protected-(D)-serine D50 prepares easily.Blocking group L is a BOC or a CBZ group easily.The benzylization of D64 can realize with well-known many methods on the document, comprising in a kind of atent solvent such as DMF, taking off proton with 2 equivalent sodium hydrides, handle (Synthesis 1989,36) with the various benzyl halides of 1 equivalent subsequently, shown in scheme D15.
This O-alkyl-(D)-serine derivative also can be with the preparation of alkylation scheme.Other method that can be used for preparing (the D)-serine derivative of general formula D 51 comprises the deutero-carboxy protective intermediate chemical formula ArCH from D50
2OC (=NH) CCl
3Reagent carry out acid catalyzed benzylization (people such as O.Yonemitsu, Chem.Pharm.Bull.1988,
36, 4244).In addition, also have chirality glycine enolate (J.Am.Chem.Soc.1991,
113, 9276:J.Org.Chem.1989,
54, 3916) and be the ArCH of leaving group with X
2OCH
2X carries out alkylation, provides D51.In addition, D, L-O-aryl (alkyl) serine can and be torn open and analyse with the above method preparation.
Be noted that in some cases, can change the carrying out order of above-mentioned each reaction scheme, be beneficial to the product of reacting or avoiding not wanted.
The compounds of this invention as the passable technical known methodology of the effectiveness of growth hormone cinogenic agent for example people such as Smith exist
Science,
260, the test described in the 1640-1643 (1992) (seeing the wherein content of Fig. 2) confirms.Specifically, all chemical compounds that prepare in the following example all have the activity as growth hormone cinogenic agent in above-mentioned test.A kind of like this result shows the intrinsic activity of The compounds of this invention as growth hormone cinogenic agent.
These can make compound of Formula I that growth hormone discharges can be under isolated condition as how understanding growth hormone secretion be adjusted in unique tools on the hypophysis level.This comprises that being used for assessment much is considered to or known to the influential factor of growth hormone secretion, as age, sex, trophic factors, glucose, aminoacid, fatty acid, and fasting state and non-fasting state.In addition, The compounds of this invention can also be used to assess other hormone and how to change activity to growth hormone release.For example, determined already that Somat (somatostatin) can suppress growth hormone and discharge.Important and its other hormone to the influence of growth hormone release of needs research comprise gonadal hormone, as testosterone, estradiol and Progesterone; Epinephrine is as hydrocortisone and other corticoid, epinephrine and norepinephrine; Pancreatic hormone and gut hormone are as insulin, glucagon, gastrin, secretin; Vasoactive peptide is as bombesin, neurokinin; And thyroxin, as thyroxine and 3.Compound of Formula I also can be used for studying some pituitary hormones such as growth hormone and endorphins hypophysis is changed possible negative feedback or the positive feedback influence that growth hormone discharges.The subcellular mechanisms that is to use these chemical compounds to illustrate to influence growth hormone to discharge with special scientific meaning.
Compound of Formula I can be to comprising people's animals administer, so that growth hormone releasing in vivo.For example, this compounds can to quicken and to increase its speed of growth and degree, improve feed efficiency and increase the milk yield of some animals like this administrations such as commercially important animal such as pig, cattle, sheep.In addition, these chemical compounds can also be to live body people administration, with this as a kind of diagnostic means of determining that directly hypophysis whether can growth hormone releasing.For example, compound of Formula I can be to the administration of child's live body.The blood serum sample of gathering before and after the administration can be used to detect growth hormone like this.The wherein comparison of growth hormone quantity in each sample can be a kind of means of ability of direct mensuration patient hypophysis growth hormone releasing.
Therefore, the present invention includes pharmaceutical composition in its scope in, wherein comprises at least a as active component of compound of Formula I, and cooperates a kind of pharmaceutical carrier or diluent.Randomly, the active component of this type of pharmaceutical composition is except that compound of Formula I at least a, can also comprise a kind of anabolic agent, or the another kind of compositions that shows different activities, allow agent (antibiotic growth permittant) or a kind of medicament for the treatment of osteoporosis as a kind of antibiosis growth, or and with a kind of corticosteroid to reduce the catabolism side effect to greatest extent, or and use the other medicines active material, wherein should and also reduce side effect to greatest extent with improving drug effect.
Growth promoter and anabolic agent include but not limited to TRH (thyrotrophin-releasing hormone), diethylstilbestrol, estrogen, beta-stimulants, theophylline, anabolic steroid, enkephalin, E series precursor parathyrine, U.S. Patent No. 3,239, disclosed chemical compound such as ZER in 345, with U.S. Patent No. 4, disclosed chemical compound such as sulbenox in 036,979, or U.S. Patent No. 4, disclosed peptide in 411,890.
The further again purposes of growth hormone cinogenic agent of the present invention is other growth hormone cinogenic agent of combination, for example U.S. Patent No. 4,411,890 and WO 89/07110, growth hormone-releasing peptide GHRP-6 described in WO 89/07111 and B-HT 920 publications such as grade, GHRP-1, and the new discovery GHRP-2 described in hexarelin and the WO 93/04081, or growth hormone releasing hormone (GHRH, be also referred to as GRF) ex hoc genus anne thing, or growth hormone ex hoc genus anne thing, or somatomedin comprises IGF-1 and IGF-2, or alpha-adrenergic aginists such as clonidine, or serotoxin 5HTID antagonist such as sumitriptan, maybe can suppress medicament such as the physostigmine and the pyridostigmine of Somat or its release.
The skilled person is well-known as this gate technique, and the known application of growth hormone and potential use are different with many-sided.The compounds of this invention can have effect or the purposes identical with growth hormone itself with the administration that stimulates endogenous growth hormone to be released to purpose.The different purposes of these of The compounds of this invention thereby can be summarized as follows: stimulate old people's growth hormone to discharge; The adult of treatment growth hormone deficiency; The catabolism side effect of prevention glucocorticoid; The treatment osteoporosis; Stimulating immune system, accelerating wound healing; The acceleration bone splits is repaired; The treatment growthing lag; Treat acute or chronic renal failure or functional defect; The treatment physiological is of short and small stature, comprises the child of growth hormone deficiency; Treat relevant with chronic disease of short and small stature; Treatment obesity and the growthing lag relevant with obesity; Treat the growthing lag relevant with Turner syndrome with the Prader-Willi syndrome; Quicken the recovery after fire victim or great surgical operation such as the gastrointestinal surgery and reduce its hospital stay; Treatment intrauterine growthing lag and skeletal development are bad, the treatment Peripheral nerve disease; Change the growth hormone of stressed patients; Treatment osteochondrodysplasia, Noonans syndrome, schizophrenia, depression, Alzheimer, delay wound healing and psychological social isolation; Treatment lung malfunction and ventilate fan rely on; The protein catabolism that alleviates after the major operation is replied; The treatment malabsorption syndrome; Reduce because cachexia that chronic disease such as cancer or AIDS cause and protein lose; Quickening recovery of TPN (complete non-enteral nutrition) weight in patients and protein increases; The treatment Hypoinsulinemia comprises the insulin cell hyperproliferative disorder; Bring out the auxiliary treatment that ovulation and control gastric ulcer and duodenal ulcer, the thymus function inner feelings relevant with the age with prevention of stimulation thymus development are moved back; Chronic hemodialysis patient's auxiliary treatment; Treatment immunosuppressant type patient, the antibody response behind the enhancing bovine vaccination; Improve the total lymphocyte number of human body, specifically, improve such as because of physical trauma such as the closure head is hindered or because of infect as antibacterial or viral infection particularly HIV (human immunodeficiency virus) infections cause T
4/ T
8Cell is than the T of human body on the low side
4/ T
8The cell ratio; Improve muscle strength, mobility, keep skin thickness, metabolism body inner equilibrium, weak old people's kidney homoiostasis; Stimulating osteoblast, remodeling and cartilage-derived growth; Stimulate immune system of companion animal and the aging imbalance of treatment companion animal; The domestic animal growth promoter; Become mildewed with stimulation sheep.In addition, The compounds of this invention can be used for improving domestic animal feed efficiency, promote growth, increase milk yield and improve body constitution.
Specifically, The compounds of this invention can be used for preventing or treats a kind of disease that is selected from as next group: osteoporosis; The catabolism disease: immunodeficiency comprises T
4/ T
8Cell is than the immunodeficiency of individuality on the low side: hip breaks; Old people's flesh skeletal injury; Adult or children growth hormone are not; Fat: cachexia that chronic disease such as AIDS or cancer cause and protein loss; With the treatment those from the patient of great surgical operation, wound or burn rehabilitation, promptly need the patient's of this type of treatment treatment.
What this gate technique skilled person will know is, it is numerous to be used for the chemical compound that the treatment of above-mentioned disease or treatment indication makes great efforts at present.These healing potions (some of them are mentioned in the above) will bring additional, that replenish and often collaborative character with the combination of growth hormone cinogenic agent of the present invention, thereby strengthen growth, anabolism and the desirable character of these different healing potions.In these combinations, these therapeutic agents and growth hormone cinogenic agent of the present invention can independently exist, and its dosage range is that one of percentage of these chemical compounds and sercretogogue effective dosage level when using separately is doubly to one times.
The combined therapy that suppresses bone resorption, prevention of osteoporosis and enhancement union of fracture can illustrate with the combination of diphosphonate and growth hormone cinogenic agent of the present invention.Diphosphonate is summarized for the use of these effectiveness is existing, for example, and Hamdy, N.A.T., Role of Bisphosphonatesin Metabolic Bone Diseases, T
Rends in Endocrinol Metab.,
4,19-25 (1993).There is the diphosphonate of these effectiveness to comprise alendronate, tilu-dronate, dimethyl-APD, risedronate, etidronate, YM-175, clodronate, pamidronate, and BM-210995.According to its effect, be to obtain effective treatment to osteoporosis, be 0.1mg~5g to the diphosphonate per os dosage level of patient's administration, growth hormone cinogenic agent dosage level of the present invention is 0.01mg/kg~20mg/kg body weight.
The compounds of this invention can via per os, non-through intestinal (as intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), per nasal, transvaginal, per rectum, through the Sublingual or through the topical administration, and can be mixed with the dosage form that is suitable for every kind of route of administration.
Peroral administration solid dosage form comprises capsule, tablet, pill, powder and granule.In such solid dosage form, can accept carrier such as sucrose, lactose or starch at least a inert medicine of reactive compound fusion.Such dosage form also routinely way comprise other added substance except that inert diluent, as lubricants such as magnesium stearate.Under the situation of capsule, tablet and pill, these dosage forms also can comprise buffer agent.Tablet and pill can also prepare with enteric coating.
Peroral administration liquid dosages form comprises on the medicine that contains technical inert diluent commonly used such as water can accept emulsion agent, solution, suspension liquor, syrup, elixir.Except that such inert diluent, compositions also can comprise accessory drugs, as wetting agent, emulsifying agent, suspending agent, sweetener, strong smelly correctives and flavouring agent.
Non-ly comprise aseptic water or non-aqueous solution agent, suspension liquor or emulsion agent according to of the present invention through the enteral administration preparation.The example of nonaqueous solvent or carrier is propylene glycol, Polyethylene Glycol, vegetable oil such as olive oil and Semen Maydis oil, gelatin and injectable organosilane ester such as ethyl oleate.Such dosage form also can contain accessory drugs, as antiseptic, wetting agent, emulsifying agent and dispersant.They can be sterilized with the following method, for example, filter by the filter that can hold back antibacterial, add biocide in compositions, irradiation compositions, or heating combination.They also can make the aseptic solid composite that can be dissolved in sterilized water or certain other sterile injectable medium before facing use.
The compositions of per rectum or transvaginal administration better is a suppository, and it can also contain excipient such as cupu oil or suppository wax except that containing active substance.
Per nasal or also be with technical well-known standard excipients preparation through the compositions of sublingual administration.
The dosage of active component can change in the present composition; Yet, be necessary to make the quantity of active component to reach the degree that can obtain a kind of suitable dose form.Selected dosage depends on desirable therapeutic effect, route of administration and treatment persistent period.In general, to patient and animal such as mammal administration, can obtain effective release of growth hormone with the dosage level of 0.0001~100mg/kg body weight.
Following example only provides for the purpose that further specifies, and is not intended in order to limit disclosed invention.As with conspicuous, titled with the example of " A " and intermediate chemical compound corresponding to first embodiment, titled with the chemical compound of " B " person corresponding to second embodiment, titled with " C " person then corresponding to the chemical compound of the 3rd embodiment.
To the commercial N-t-BOC-D-tryptophan (25.0g that gets, 82.2mmol), benzylalcohol (10.2ml, 98.6mmol) and dichloromethane (200ml) solution of DMAP (100mg) in, 0 ℃ with one hour time divide some batches add EDC (17.4g, 90.4mmol).Reactant mixture was stirring at room 6 hours.In the impouring water (200ml), separate organic layer.Organic solution is used anhydrous magnesium sulfate drying with the mixed liquor washing of saline and 3N hydrochloric acid, filters and concentrates, and provides a kind of thick shape oil, solidifies when leaving standstill.
In this oily 30ml dichloromethane solution, add 20ml TFA, stirred 1 hour.Reactant mixture concentrates, and carefully neutralizes with saturated sodium bicarbonate aqueous solution, with dichloromethane (2 * 100ml) extractions, the organic solution that merges is washed with saline (100ml), by short silicagel column, the 5-10% methanol-eluted fractions with in the dichloromethane provides 23.2g oily amine after the evaporation.
To the said goods, HOBT (10.6g, 78.8mmol) and N-BOC-Alpha-Methyl alanine (19g, in 200ml dichloromethane solution 94.5mmol), some batches of 0 ℃ of branches add EDC (19.5g, 0.102mol).After 5 minutes, limpid reactant mixture becomes milky.After stirred overnight at room temperature, in the reactant mixture impouring 200ml water, separate organic layer.Organic solution salt water washing, anhydrous magnesium sulfate drying is used in reuse saline and saturated sodium bicarbonate solution washing, filters and concentrates.Provide a kind of thick shape oil, reuse dodges anxious chromatography purification, with 10~40% ethyl acetate gradient elutions in the hexane, provides expection material (28.7g).
1H?NMR(CDCl
3,200MHz)δ8.48(br.s,1H),7.54(br.d,1H),7.38-7.23(m,3H),7.19(br.d,2H),7.15-7.00(m,1H),6.90(d,1H),6.86(d,1H),5.06(br.s,2H),4.95(ddd,1H),3.30(2dd,2H),1.40(s,15H)
The solution of the material that step B obtains (28.7g) in 200ml ethanol 10% charcoal carry palladium (2g) in the presence of, at H
2Under the atmosphere, stirring at room 20 minutes.Catalyst leaches with diatomite layer, washs with ethyl acetate.Filtrate concentrates, and provides rose pink cystose acid (23.3g).
1H NMR (CD
3OD, 400MHz) δ 7.56 (d, J=8Hz, 1H), 7.31 (dd, J=1,8Hz, 1H), 7.09 (s, 1H), 7.07 (dt, J=1,7Hz, 1H), 6.98 (dt, J=1,7Hz, 1H), 4.69 (t, J=6Hz, 1H), 3.34-3.23 (m, 2H), 1.35 (s, 3H), 1.34 (s, 9H), 1.29 (s, 3H) .FAB-MS value of calculation C
20H
27N
3O
5: 389; Measured value 390 (M+H), 290 (M+H-100 (BOC)).
Intermediate 2
Replace the N-t-BOC-D-tryptophan with N-t-BOC-O-benzyl-D-serine, carry out, provide intermediate 2 according to the preparation process of intermediate 1.FAB-MS value of calculation C
19H
28N
2O
6: 380; Measured value 381 (M+H), 325 (M+H-56 (t-Bu)), 281 (M+H-100 (BOC)).
Steps A: (DL)-N-acetyl-2-amino-5-phenyl valeric acid
In room temperature, under blanket of nitrogen, (2.3g adds diethyl acetamido in ethanol 0.1mol) (60ml) solution to sodium.Mixture drips 1-bromo-3-phenyl-propane then stirring at room 1 hour, and after the interpolation, mixture refluxes then and spends the night stirring at room 2 hours.It is cooled to room temperature, makes it between water and ethyl acetate, to distribute.Organic layer washs with sodium bicarbonate aqueous solution, uses MgSO
4Drying, evaporation provides a kind of intermediate (32.5g, 97%).
1H?NMR(CDCl
3,400MHz)7.26-7.10(m,5H);6.75(br.s,1H);4.19(q,J=7Hz,4H);2.58(t,J=7.9Hz,2H);2.39-2.35(m,2H);2.00(s,3H);1.43-1.39(m,2H);1.20(t,J=7Hz,6H).
Above-mentioned product is suspended in the 190ml 2.5N NaOH aqueous solution, refluxes 2 hours.Mixture is cooled to 0 ℃, it carefully is neutralized to pH2 with 6N HCl.Precipitate is collected with sintered glass funnel, uses a small amount of cold water washing, and is air-dry.Then with solid suspension in 300ml water, refluxed 4 hours.Solution is cooled off, is acidified to pH1, collect solid (15.3g, 67%) with Filtration.
1H?NMR(CD3OD,400MHz)7.26-7.12(m,5H);4.90-4.37(m,1H);2.65-2.60(m,2H);1.97(s,3H);1.87-1.82(m,1H);1.73-1.65(m,3H).
Step B:(D)-N-acetyl-2-amino-5-phenyl valeric acid
The racemic intermediate that previous step obtains suddenly (10g, 42.5mmol) and CoCl
36H
2O is dissolved in 21ml 2N KOH and the 200ml water at 40 ℃, adds several 2N KOH the pH of solution is transferred to 8.Under fierce the stirring, add acyltransferase I (aspergillosis (As-pergillus sp.), 0.5u/mg, Sigma corporate system then; 0.9g).Reactant mixture stirred 1 day at 40 ℃, made pH remain on 8 by adding a few drops KOH.Formed solid is leached.Filtrate is acidified to pH2 with 3N HCl, with ethyl acetate (200ml * 4) extraction.Organic extract merges, evaporation, provides a kind of white solid (4.64g, 46%).
1H?NMR(CD3OD,400MHz)7.26-7.12(m,5H);4.90-4.37(m,1H);2.65-2.60(m,2H);1.97(s,3H);1.87-1.82(m,1H);1.73-1.65(m,3H).
Step C:(D)-N-t-BOC-2-amino-5-phenyl valeric acid
(4.2g 17.8mmol) is suspended among the 2N HCl (100ml) intermediate that step B obtains, and refluxes 2 hours.Reactant mixture vacuum evaporation produces a kind of white solid to remove water and hydrochloric acid.In this solid 50ml aqueous solution, add 3N NaOH up to pH11, under fierce the stirring, add then Bis(tert-butoxycarbonyl)oxide (4.66g, 21.4mmol).After 4 hours, reactant mixture is acidified to pH2 with 3N HCl, with ethyl acetate (100ml * 3) extraction.Organic extract merges, evaporation, provides a kind of white solid (6.56g, thick product), need not purification during use.
1H?NMR(CD3OD,400MHz)7.26-7.12(m,5H);4.11-4.08(m,1H);2.65-2.60(m,2H);1.83-1.62(m,4H);1.43(s,9H).
Replace the N-t-BOC-D-tryptophan with (D)-N-t-BOC-2-amino-5-phenyl valeric acid, carry out, provide intermediate 3 according to the preparation process of intermediate 1.
1H?NMR(CDCl
3,400MHz)7.24-7.20(m,2H),7.15-7.04(m,3H),4.60-4.55(m,1H),2.62-2.55(m,2H),2.00-1.86(m,1H),1.78-1.60(m,3H),1.50(s,6H),1.30(s,9H).
Example A1
Steps A:
At 0 ℃, in dichloromethane (80ml) solution of (dl)-pipecolinic acid ethyl ester (1g), HOBT (860mg) and intermediate 1 (2.47g), add EDC (2.3g).Reactant mixture is in stirred overnight at room temperature.This solution is water, saturated sodium bicarbonate solution and saturated nacl aqueous solution washing respectively, uses anhydrous magnesium sulfate drying; Filter then and concentrate, provide a kind of crude product.This crude product MPLC purification, with 60% eluent ethyl acetate in the hexane, the product that provides is the mixture (2.79g) of two kinds of diastereomers.This mixture of 500mg separates, uses 50% eluent ethyl acetate in the hexane with MPLC, produces two kinds of single diastereomers.The diastereomer that comes out earlier from this post is called d
1(187mg), the spatial chemistry that proved this pipecolinic acid ester afterwards is the R configuration.After the diastereomer that comes out be called d
2(116mg), the spatial chemistry of its pipecolinic acid ester is the S configuration.In addition, also have some to mix fraction,, obtain 190mg d its merging, evaporation
1And d
2Mixture.d
1: FAB-MS value of calculation C
28H
40N
4O
6: 528; Measured value: 529 (M+H) d
2: FAB-MS value of calculation C
28H
40N
4O
6: 528; Measured value: 529 (M+H)
Step B:
The compound d that steps A obtains
1Ethyl acetate (140mg) (5ml) solution is cooled to 0 ℃.In this mixture, feed hydrogen chloride gas while stirring, until reaching capacity.Reactant mixture stirred 15 minutes.With solution concentration, remove ethyl acetate then.Then residue is dissolved in dichloromethane and the hexane again, vacuum evaporation subsequently provides solid, shaped product (110mg).FAB-MS value of calculation C
23H
32N
4O
4: 428; Measured value: 429 (M+H)
1H NMR (400MHz, CD
3OD): chemical compound exists with the form of mixtures of rotamer (about 2: 1).
7.57(d,1H),7.36&7.32(2d,1H),7.14-7.00(m,3H),5.30-5.20(m),5.17-5.13(m),4.36(d),4.21(q,J=7Hz),4.13(q,J=7Hz),4.00(md),3.35-3.04(m),2.60(dt),3.30(br.d),2.70-2.50(m),1.57(s),1.55(s),1.52(s),1.50-1.20(m),1.33(s),1.27(t,J=7Hz),1.21(t,J=7Hz),1.15-1.10(m),0.75-0.65(m),0.30-0.20(m).
Example A2
With the intermediate (40mg) and the HCl gas that obtain from example A1 steps A,, in ethyl acetate (3ml), prepare according to step described in the example A1 step B at 0 ℃.Product: 28mg.FAB-MS value of calculation C
23H
32N
4O
4: 428: measured value: 429 (M+H)
1H NMR (400MHz, CD
3OD): chemical compound exists with the form of mixtures of rotamer (about 5: 1).
7.56(d,J=8Hz?5/6H),7.50(d,1/6H),7.34(d,J=8Hz,5/6H),7.31(d,1/6H),7.12-7.00(m,3H),5.28(dd,5/6H),5.15-5.11(m,1/6H),5.11-5.07(m,1/6H),5.02-4.98(m,5/6H),4.52-4.45(m),4.12(q,J=7Hz),4.25-4.00(m),3.65(m),3.30-3.05(m),2.80-2.70(m),2.32-2.25(m),2.02-1.97(m),1.75-1.65(m),1.57(s),1.52(s),1.51(s),1.40-0.85(m),1.22(t,J=7Hz),0.41-0.30(m).
At 0 ℃, under agitation, to L-proline benzyl ester hydrochloride (155mg, 0.64mmole), intermediate 1 (250mg, 0.64mmol), HOBT (1 equivalent) and NMM (0.07ml, add in dichloromethane solution 0.64mmole) EDC (246mg, 1.28mmole).Reactant mixture spends the night 0 ℃ of stirring, is allocated in then between 3N HCl and the ethyl acetate.Organic layer usefulness saline and saturated sodium bicarbonate solution washing, dry, evaporation.With the MPLC purification of 50% eluent ethyl acetate, provide intermediate tripeptide benzyl ester (338mg, 91.5%).FAB-MS value of calculation C
32H
40N
4O
6: 576; Measured value: 577 (M+H)
According to the step described in the example A1 step B, use the intermediate (280mg) and the HCl gas that obtain suddenly from previous step 0 ℃ ethyl acetate (10ml), to prepare.Response time: 25 minutes.Product: 218mg.FAB-MS value of calculation C
27H
32N
4O
4: 476; Measured value: 477 (M+H)
1HNMR (400MHz, CD
3OD): 8.20 (d), 7.54 (d, J=7.9Hz, 1H) 7.34-7.00 (m, 9H), 5.11 (dd, J=4.2Hz, 16.5Hz, 2H), 4.99-4.94 (m, 1H), and 4.23-4.20 (m, 1H), 3.58-3.53 (m, 1H), and 3.31-3.13 (m, 2H), 2.77-2.75 (m, 1H), 1.71-1.60 (m, and 3H) 1.55 (s, 3H), 1.51 (s, 3H), 1.37-1.33 (m, 1H).
Steps A: (dl)-pipecolinic acid benzyl ester
(dl)-toluene (200ml) solution of pipecolinic acid (25g), p-methyl benzenesulfonic acid (38g) and benzylalcohol (84g) refluxed one day under the azeotropic condition.This solution is cooled to room temperature, collects the crystallization that is produced, and provides desirable product (52.4g).Product with 3N NaOH washing to remove toluenesulfonic acid, then in ethyl acetate with the HCl gas reaction, make it to change into hydrochlorate.
According to the step described in the example A3 steps A, from (dl)-pipecolinic acid benzyl ester hydrochloride (3.5g), intermediate 1 (5.00g), HOBT (1.74g), NMM (1.42ml) and EDC (3.94g) preparation.Product: 6.32g.FAB-MS value of calculation C
33H
42N
4O
6: 590: measured value: 591 (M+H)
According to the step described in the example A1 step B, use the intermediate (250mg) and the HCl gas that obtain suddenly from previous step 0 ℃ acetas, to prepare, provide title compound (211mg).FAB-MS value of calculation C
28H
34N
4O
4: 490: measured value: 491 (M+H)
Product (5.3g) that obtains from example A4 step B and 10% charcoal carry the suspension of palladium (270mg) ethanol (100ml) and stirred 3 hours under nitrogen atmosphere.Reactant mixture provides this acid (4.48g) with diatomite filtration, evaporation.
Similarly according to the described step of example A3 steps A, with the sour intermediate (200mg) that obtains suddenly from previous step, ethylamine hydrochloride (27mg), HOBT (54mg), NMM (0.07ml) and EDC (154mg) preparation, provide the mixture of two kinds of diastereomers, the MPLC of reuse eluent ethyl acetate separates.D is appointed as in the isomer of coming out earlier from this post
1(76mg), d is appointed as in second isomer of coming out
2(165mg).d
1FAB-MS value of calculation C
28H
41N
5O
5: 527; Measured value: 528 (M+H) d
2FAB-MS value of calculation C
28H
41N
5O
5: 527; Measured value: 528 (M+H)
Step C:
According to step described in the example A1 step B, use the intermediate (d that a step obtains similarly
1) (60mg) prepare in 0 ℃ ethyl acetate (5ml) with HCl gas, provide title compound (38mg).Response time: 20 minutes.FAB-MS value of calculation C
23H
33N
5O
3: 427; Measured value: 428 (M+H)
1HNMR (400MHz, CD
3OD): d7.63-7.00 (m, 5H), 5.33 (t), 5.40-5.25 (m), 5.11-5.09 (m), 4.32 (br.d), 4.16-4.12 (m), 4.00 (md), 3.35-3.03 (m), 2.96 (q, J=7Hz), 2.30 (dt), 2.19 (br.d), 1.95-1.40 (m), 1.66 (s), 1.64 (s), 1.40-1.20 (m), 1.20-1.00 (m), 1.12 (t, J=7Hz), 1.03 (t, J=7Hz), 0.65-0.52 (m) ,-0.44--0.53 (m).
Example A6
Similarly according to the step described in the example A1 step B, with the intermediate (d among the example A5 step B
2) (100mg) prepare in 0 ℃ ethyl acetate (5ml) with HCl gas, provide title compound (78mg).Response time: 20 minutes.FAB-MS value of calculation C
23H
33N
5O
3: 427; Measured value: 428 (M+H)
1HNMR (400MHz, CD3
OD): d7.54 (d, J=8Hz, 1H), 7.35 (d, J=8Hz, 1H), 7.16 (s, 1H), 7.13-7.00 (m, 2H), 4.98 (dd, J=6Hz, 10Hz), 4.93 (d, 4Hz), 3.53 (br.d, J=12Hz, 1H), 3.35-3.22 (m), 3.14-3.09 (m, 1H), 2.85 (dt, J=3,13Hz, 1H), 2.02 (br.d, J=12Hz), 1.65 (s, 3H), 1.61 (s, 3H), 1.10 (t, 7Hz, 3H), 1.05-0.92 (m, 2H), 0.72-0.62 (m, 1H) ,-0.25--0.30 (m, 1H).
Steps A:
According to the step described in the example A3 steps A, with L-ethyl prolinate hydrochlorate (115mg, 0.642mmole), intermediate 1 (250mg, 0.642mmole), HOBT (1 equivalent), NMM (0.07ml, 0.642mmole) and EDC (246mg, 1.28mmole) preparation.Product: 330mg.FAB-MS value of calculation C
27H
40N
4O
6: 514; Measured value: 515 (M+H)
According to the step described in the example A1 step B, use the intermediate (280mg) and the HCl gas that obtain suddenly from previous step 0 ℃ ethyl acetate (10ml), to prepare.Response time: 25 minutes.Product: 220mg.FAB-MS value of calculation C
22H
32N
4O
4: 414; Measured value: 415 (M+H)
1HNMR (400MHz, CD
3OD): 7.53 (d, J-7.9Hz, 1H), 7.34 (d, J-8.1Hz, 1H), and 7.14-7.01 (m, 3H), 4.97-4.84 (m, 1H), 4.15-4.06 (m, 3H), 3.60-3.53 (m, 1H), 3.31-3.13 (m, 2H), and 2.77-2.72 (m, 1H), 1.72-1.59 (m, 3H), 1.57 (s, 3H), 1.50 (s, 3H), 1.36-1.27 (m, 1H), 1.23 (t, J=7.1Hz, 3H).
Steps A: 2-cyano group-1-hydroxy-4-phenyl piperidine
(10g 0.062mole) adds sodium tungstate dihydrate (0.82g, water 2.48mmole) (7ml) solution in methanol (30ml) solution to the 4-Phenylpiperidine that stirs.0 ℃ of stirring, and the dropping hydrogen peroxide (30%, 13.9ml, 0.136mole).After interpolation is finished, reactant mixture restir 3 hours.Add then Cyanogran. (4.56g, 0.093mole) add subsequently 4N HCl (22ml, 0.088mole).Reactant mixture stirs and spends the night, and makes it to room temperature during this period.Collect solid with glass sintering funnel Filtration, solution is neutralized to pH7, use dichloromethane extraction.Organic extract and solid merge, and use MgSO
4Dry, evaporation.With dodging anxious chromatographic column purification,, provide 2-cyano group-1-hydroxy-4-phenyl piperidine (8.6g) with 40% eluent ethyl acetate in the hexane.
1HNMR(400MHz,CDCl
3):7.35-7.17(m,5H),6.01(br.s,1H),4.34(br.s,1H),3.31(td,J=3,11Hz,1H),3.09(dt,J=11,3Hz,1H),2.93-2.86(m,1H),2.20-2.10(m,2H),1.97-1.80(m,2H).
Step B:2-cyano group-4-Phenylpiperidine
To methanol (10ml) solution, add TiCl at intermediate stirring at room, that obtain suddenly from previous step (500mg)
3(10% solution in 20-30% hydrochloric acid) (3ml).Mixture stirred 15 minutes, added 3NNaOH and made it neutralization.Residue dichloromethane extraction 4 times, organic extract merges, and uses MgSO
4Dry, evaporation provide 450mg 2-cyano group-4-Phenylpiperidine, need not to be further purified promptly and use.
Step C:
According to the step of example 3A steps A, use the intermediate that a step obtains, two kinds of chemical compounds are provided after the MPLC purification with 60% eluent ethyl acetate in the hexane.The chemical compound that comes out earlier from post is appointed as diastereomer 1, and another kind is appointed as diastereomer 2.d
1: FAB-MS value of calculation C
32H
39N
5O
4: 557; Measured value: 558 (M+H) d
2: FAB-MS value of calculation C
32H
39N
5O
4: 557; Measured value: 558 (M+H)
According to the experimental procedure of example A1 step B, use product and the HCl gas that a step obtains and in 0 ℃ ethyl acetate, prepare, provide the expection product.d
1: FAB-MS value of calculation C
27H
31N
5O
2: 457: measured value: 458 (M+H) d
2: FAB-MS value of calculation C
27H
31N
5O
2: 457: measured value: 458 (M+H)
Example A9
Steps A: 2-cyano group-4-phenylpyridine
To at the 4-of stirring at room phenylpyridine-N-oxide (25g, 0.146mmol) dichloromethane (200ml) solution in add trimethyl silyl cyanogen (17.4g), add dichloromethane (50ml) solution of dimethylcarbamyl chloride (16.2ml) subsequently slowly with 30 fens clock times.Reactant mixture is stirring at room 1 day, then to wherein add slowly solution of potassium carbonate (10%, 150ml).Stir and continued again 30 minutes, separate organic layer, the water layer dichloromethane extraction.Extract is merged, use dried over mgso.Vacuum evaporation provides crude reaction product (35g), and solid, shaped is white in color.Need not to be further purified and to use.FAB-MS value of calculation C
12H
8N
2: 180; Measured value: 181 (M+H) 1HNMR (400MHz, CD3OD): 8.71 (dd, 1H), 8.19 (dd, 1H), 7.94 (dd, 1H), 7.81-7.78 (m, 2H), 7.56-7.50 (m, 3H).
Step B:4-phenylpyridine-2-carboxylic acid
The 100ml 6N HCl solution of the product that previous step obtains suddenly (25g) refluxed 1 day.Make this solution cool to room temperature, crystallization this moment begins to take place.Crystal is filtered, collects, provide product (27.5g, 87%).
Step C:4-phenylpyridine-2-carboxylic acid, ethyl ester hydrochlorate
Upwards the intermediate of step preparation (5.0g, 21.2mmol), add EDC (1.5 equivalent) in the dichloromethane solution of ethanol (2g), DMAP (20mg) and N-methylmorpholine (1 equivalent).Reactant mixture spends the night 0 ℃ of stirring.This solution washs, uses anhydrous magnesium sulfate drying with saturated sodium bicarbonate solution; Filter then, concentrate.Use the MPLC purification,, provide 4-phenylpyridine-2-carboxylic acid, ethyl ester (3.71g, 77%) with 40% eluent ethyl acetate in the hexane.This chemical compound is used the HCl gas treatment in ethyl acetate, evaporation changes into its HCl salt subsequently.
Step D:4-Phenylpiperidine-2-carboxylic acid, ethyl ester
Product that previous step obtains suddenly (200mg) and the suspension of dioxy platinum (20mg) in ethanol stirred 3 hours under nitrogen atmosphere.Then, reactant mixture is by diatomite filtration, evaporation.Resulting material need not to be further purified and can use.
Step e:
At 0 ℃, upwards add EDC (1.5 equivalent) in the dichloromethane solution of the intermediate (200mg) of step preparation and intermediate 1 (1 equivalent), HOBT (1 equivalent) and NMM (1 equivalent).Reactant mixture spends the night 0 ℃ of stirring.This solution washs with saturated nacl aqueous solution, uses anhydrous magnesium sulfate drying, filters, and concentrates then.Use the MPLC purification, 50% eluent ethyl acetate with in the hexane provides the chemical compound that is the non-enantiomer mixture form.
Step F:
In ethyl acetate (2ml) solution, feed HCl gas, until reaching capacity at intermediate 0 ℃ of stirring, that previous step obtains suddenly (30mg).Reactant mixture stirred 15 minutes, was evaporated to driedly, provided product.FAB-MS value of calculation C
29H
36N
4O
4: 504; Measured value: 505 (M+H)
Other products shown in the Table A I are according to example A9 step e and F, the intermediate preparation that obtains with intermediate 2 or intermediate 3 and step D.
Sequence number
Product R
1MF
FAB-MS(M+1)
1??????Ph(CH
2)
3-???????C
29H
39N
3O
4
494
2??????PhCH
2OCH
2-??????C
28H
37N
3O
5
496
Equally, chemical compound shown below is promptly introduced 2-cyano group substituent group in various replacement 4-phenylpyridine that obtains easily according to example A9 preparation, the separating isomerism body with posthydrolysis, has anhydrous acidic ethyl ester resterification in case of necessity, with the pyridine ring hydrogenation, prepare following intermediate:
These can react with intermediate 1 or 3, provide following compounds respectively.
Steps A: 3-benzyl pyridine-N-oxide
The 3-benzyl pyridine (25g, 0.148mol) hydrogen peroxide (30%, 15.1ml) and the solution in the acetic acid (100ml) refluxed 1 day.And then adding hydrogen peroxide (3ml), the mixture that is generated refluxes and spends the night.Then reactant mixture is evaporated, and be allocated between the mixture of 3NHCl, saline and dichloromethane.Organic layer separates, dry, evaporation, provides expecting compound (27.6g, 100%).
Step B:3-benzyl-2-cyanopyridine
According to the step of example A9 steps A, use intermediate (27g) preparation that a step obtains.Crude reaction product SiO
2Dodge anxious chromatographic column purification,, provide 5-benzyl-2-cyanopyridine (3.0g, 10%) and 3-benzyl-2-cyanopyridine (24.2g, 85%) with the 20-40% eluent ethyl acetate in the hexane.
Step C:3-benzyl pyridine-2-carboxylic acid hydrochloride
The solution of 3-benzyl-2-cyanopyridine (19.1g) in concentrated hydrochloric acid (50ml) and water (50ml) refluxed 2 days.Resulting solution evaporation provides a kind of solid (30.1g, 100%, wherein contain the ammonium chloride of equimolar amounts).
Step D:3-benzyl pyridine-2-carboxylic acid, ethyl ester hydrochlorate
Thionyl chloride (15.2g) carefully is dissolved in the ethanol (300ml), and the solution of formation adds in the intermediate (20g) that previous step obtains suddenly.Mixture refluxes and spends the night, and evaporates then, provides the crude product of hydrochloride form.This crude product is dissolved in the dichloromethane, washs with saturated sodium bicarbonate solution.Organic solution drying, evaporation are with short SiO
2Column purification provides the product (18.2g) of free alkali form.In ethyl acetate (80ml) solution of this intermediate (16.5g), feed HCl gas, until reaching capacity.With the mixture evaporation, provide HCl salt (18.9g) then.
Step e: 3-benzyl piepridine-2-carboxylic acid, ethyl ester hydrochlorate
Product that previous step obtains suddenly (1.0g) and the suspension of platinum dioxide (100mg) in ethanol stirred 5 hours under nitrogen atmosphere.Then reactant mixture is passed through diatomite filtration, evaporation, provide expecting compound.
Step F:
At 0 ℃, upwards (180mg adds EDC (1.5 equivalent) in the dichloromethane solution of intermediate 1 0.634mmol) (1 equivalent), HOBT (1 equivalent) and NMM (1 equivalent) to the intermediate of step preparation.Reactant mixture spends the night 0 ℃ of stirring.This solution washs with saturated nacl aqueous solution, uses anhydrous magnesium sulfate drying; Filter then, concentrate.Use the MPLC purification,, provide two kinds of enantiopure compound with 50% eluent ethyl acetate in the hexane.The chemical compound that comes out earlier from post is appointed as d
1(146mg): second chemical compound that comes out is appointed as d from post
2(141mg).d
1FAB-MS value of calculation C
35H
46N
4O
6: 618: measured value: 619 (M+H) d
2FAB-MS value of calculation C
35H
46N
4O
6: 618; Measured value: 619 (M+H)
To at intermediate d 0 ℃ of stirring, that previous step obtains suddenly
1Feed HCl gas in ethyl acetate (130mg) (2ml) solution, until reaching capacity.Reactant mixture stirred 15 minutes, it was evaporated to dried, provided product (111mg, 95%).FAB-MS value of calculation C
30H
38N
4O
4: 518: measured value: 519 (M+H)
This chemical compound is according to the rapid step of previous step, the intermediate d that obtains with step F
2(130mg) prepare.Product: 114mg, 98%.FAB-MS value of calculation C
30H
38N
4O
4: 518: measured value: 519 (M+H)
Other products shown in the Table A II are according to example A10 step F and G, the intermediate preparation that obtains with intermediate 2 or intermediate 3 and step e.During the MPLC of BOC precursor purification, do not observe the separation of diastereomer.
Product
Sequence number R
1MF
FAB-MS(M+1)
1??????Ph(CH
2)
3-?????C
30H
41N
3O
4
508
2??????PhCH
2OCH
2-????C
29H
39N
3O
5
510
Steps A: piperidines-2,3-(cis)-diethyl dicarboxylate
Hydrogen chloride gas is fed in the ethanol (400ml) until absorbing 22g.Pyridine-2,3-dicarboxylic acids (100g) is dissolved in this solution, and formed mixture refluxes and spends the night.Reactant mixture is divided into two parts, each part all with PtO
2(1.4g) together, on the Parr shaking machine, under 40psi hydrogen, shook 8 hours.Reactant mixture merges, passes through diatomite filtration, uses a large amount of washing with alcohol.Evaporation provides a kind of gray solid, and the washing of reuse ethyl acetate provides a kind of white solid (7.8g) after the filtration.
Step B:
This chemical compound is according to example A1 steps A, uses intermediate (178mg) that a step obtains and intermediate 1 preparation.Product: 234mg; FAB-MS value of calculation C
31H
44N
4O
8: 600; Measured value: 601 (M+H)
This chemical compound is the step according to example A1 step B, uses intermediate (230mg) preparation that a step obtains.Product: 215mg.FAB-MS value of calculation C
26H
36N
4O
6: 500: measured value: 501 (M+H), 523 ((M+Na)
Other intermediate shown in the Table A III are to prepare as example A11 steps A is illustrated with corresponding pyridine analogs according to the above method of setting up from corresponding pyridine derivate, and end product is according to step B and C preparation.
Product
Intermediate (QH) product
Sequence number MF MF
FAB-MS (M+1) FAB-MS (M+1)
A: this intermediate makes its all cis-isomer generation epimerization preparations with KHMDS in THF.
Steps A: N-BOC-piperidines-(cis)-2,3-diethyl dicarboxylate
Under agitation, (10g 37.6mmol) and in dichloromethane (50ml) solution of triethylamine (6.4ml) adds Bis(tert-butoxycarbonyl)oxide (10.7g) to the intermediate that obtains to example A11 steps A, and formed mixture is in stirred overnight at room temperature.Reactant mixture dilutes with dichloromethane, with 3N HCl and the washing of brinish mixed liquor.Organic layer drying, evaporation, use the silicagel column purification,, provide expecting compound (9.61g) with the gradient elution of 10-30% ethyl acetate in the hexane.
Step B:
Under argon atmospher, (3.79g in THF 19mmol) (150ml) solution, adds N-BOC-piperidines-(cis)-2,3-diethyl dicarboxylate (5g, a kind of solution 15.2mmol) with 30 fens clock times to the KHMDS-78 ℃ of stirrings.Allow this solution-78 ℃ of restir 30 minutes; In this solution, add slowly then benzyl bromide a-bromotoluene (2.73g, 15.9mmol).Reactant mixture stirs and spends the night, and makes it to room temperature.This material is concentrated, and dilute with water extracts with ethyl acetate (100ml) then.Organic layer anhydrous magnesium sulfate drying, filtration, concentrated.Dodge anxious column chromatography purification with silica gel, 20% eluent ethyl acetate with in the hexane provides two kinds of diastereomers.The chemical compound that comes out earlier from this post is appointed as d
1(1.01g); And second chemical compound that comes out is appointed as d from this post
2(3.75g).NMR determines that these esters are d
1For trans, d
2Be cis.
Step C:
These chemical compounds are the steps according to example A1 step B, use intermediate preparation that a step obtains.Intermediate d
1(850mg) produce d
1Title compound (711mg, 98%).Intermediate d
2(3.2g) produce d
2Title compound (2.58g, 96%).d
1FAB-MS value of calculation C
18H
25NO
4: 319: measured value: 320 (M+H) d
2FAB-MS value of calculation C
18H
25NO
4: 319; Measured value: 320 (M+H)
These chemical compounds are the steps according to example A1 steps A, use intermediate preparation that a step obtains.Intermediate d
1(228mg) mixture (128mg, 30%) of the trans diastereomer of generation.Intermediate d
2(228mg) mixture (164mg, 30%) of generation cis diastereomer.
These chemical compounds are the steps according to example A1 step B, use intermediate preparation that a step obtains.Intermediate d
1(120mg) produce trans (d
1) title compound (106mg, 97%) of non-enantiomer mixture form.Intermediate d
2(155mg) produce cis (d
2) title compound (135mg, 96%) of non-enantiomer mixture form.d
1FAB-MS value of calculation C
33H
42N
4O
6: 590: measured value: 591 (M+H) d
2FAB-MS value of calculation C
33H
42N
4O
6: 590; Measured value: 591 (M+H)
Other intermediate shown in the Table A IV are to prepare illustrated in example A12 steps A, B and C with the N-BOC intermediate of Table A III according to the above method of setting up, and end product is according to step D and E preparation.
Table A IV: additional example
Product
Intermediate (QH) product
Sequence number MF MF
FAB-MS(M+1)????????FAB-MS(M+1)
Equally, chemical compound shown below promptly carries out alkylation and provides following intermediate with 2-pyrmethyl chloride or 4-bromomethyl thiazole according to example A12 preparation:
Then, can make these intermediate and intermediate 1 or 2 reactions, provide following compounds respectively:
Steps A:
Under stirring at normal temperature, to dl-2-piperidines amide groups ethanol (100mg, 1.16mmol), HOBT (78.38mg, 1.16mmol) and intermediate 1 (226.12mg, 1.16mmol) dichloromethane (3ml) solution in add the 4-methyl morpholine (63.8ml, 1.16mmol).Mixture is cooled to 0 ℃, to wherein add EDC (222.3mg, 2.32mmol).Reactant mixture was stirring at room 16 hours.After the evaporation, residue is distributed in ethyl acetate and the 1N hydrochloric acid.Organic layer with dried over mgso, filtration, is evaporated to a kind of oily foams with saturated sodium bicarbonate solution, salt water washing, and reuse prepares TLC, and (acetone/chloroform: 3/7) purification provides 91mg product (R
f=0.45).CI-MS value of calculation C
28H
41N
5O
6: 543; Measured value: 544 (M+H)
1H NMR (400MHz, CDCl
3): δ 8.35 (br.s, 1H), 7.57 ﹠amp; 7.55 (2s, 1H), 7.35,7.33, (2s, 2H), 7.17 (t, J=6.95Hz, 1H), 7.15-7.07 (m, 3H), 7.03 (distorted t, J=4.95Hz, 1H), 5.16 (d, J=4.68Hz, 1H), 4.94 (m, 2H), 3.65 (m, 2H), 3.55-3.10 (m, 5H), 2.9-2.62 (m, 4H), and 2.3-2.2 (m, 1H), 1.43,1.46 and 1.41 (3s, total 15H), 1.00 (m, 1H), 0.83 (m, 1H).
Step B:
According to the experimental procedure of example A1 step B, use product and the HCl gas that a step obtains and in 0 ℃ ethyl acetate, prepare.CI-MS value of calculation C
23H
33N
5O
4: 443: measured value: 444 (M+H)
1H NMR (400MHz, CD
3OD): δ 7.54 (d, J=7.7Hz, 1H), 7.36 (d, J=8.1Hz), 7.12 (distorted t, J=7.5Hz, 1H), 7.03 (distorted t, J=7.5Hz, 1H), 4.97-4.92 (m, 1H), 3.63 (m, 1H), 3.75 (br.d, 1H), 2.82 (br.t, J=2.3Hz, 1H), 2.07 (br.d, J=2.3Hz, 1H), 1.66-1.57 (m, 6H), 1.55-0.88 (m, 4H), 0.70-0.55 (m, 1H).
Other chemical compounds shown in the Table A V prepare with intermediate 1 according to steps A and B.These piperidines intermediate or commercial getting, or be according to the method for above foundation or literature method preparation.
Table A V: additional example
Product
W MF FAB (or CI)-MS
(M+1)1????-CO
2CH
3???????????????C
22H
30N
4O
4????4152????-CONH(CH
2)
2OH?????????C
23H
33N
5O
4????4443????-CONHCH
2C(CH
3)
2OH????C
25H
37N
5O
4????4724????-CONHCH
2CH(OH)CH
3?????C
24H
35N
5O
4????4585????-CO
2NH
2???????????????C
21H
29N
5O
3????399(EI,M
+)6????-CH
2COCH
3?????????????C
23H
32N
3O
4????4137????-CH(OH)Ph-p-Cl???????????C
27H
33N
4O
3Cl??4978????-CH(OH)CH
2CH
3?????????C
23H
34N
4O
3????4159????-CONHBn??????????????????C
28H
35N
5O
3????49010???-CONH(CH
2)
2CH
3???????C
24H
35N
5O
3????44211????
????C
25H
37N
5O
3????456
12???-CONHPh????????????C
27H
33N
5O
3??????476
14
?????C
23H
30N
6O
3?????439
Other chemical compounds shown in the Table A Va are according to steps A and B, with some used in intermediate 3 and last table intermediate preparation.
Product
W MF FAB (or CI)-MS
(M+1)1????-CO
2CH
2CH
3?????????C
23H
35N
3O
4??????4182????-CONHCH
2C(CH
3)
2OH??C
25H
40N
4O
4??????4613????-CONH(CH
3)
2?????????C
23H
33N
5O
3??????4284????-CH(OH)Ph-p-Cl?????????C
27H
36N
3O
3Cl????486
In the 7.0g dihydropyran solution of 7.0g 2-bromobenzyl alcohol, add 2 concentrated hydrochloric acid in room temperature, stirring at room 1 hour.Reactant mixture is used saturated NaHCO with the dilution of 150ml ether
3(2 * 100ml), saline (150ml) washing, use MgSO
4Drying concentrates, and provides a kind of thick grease.Residue is eluant with dodging anxious chromatography purification with hexane-EtOAc, provides 10g THP trtrahydropyranyl ether.
In-78 ℃ 260ml dry diethyl ether, add 23.6ml 1.6M nBuLi hexane solution.In this solution, add the 100ml diethyl ether solution of 7.5g THP chemical compound, stirred 30 minutes ,-40 ℃ of restir 30 minutes at-78 ℃.This drips of solution is added in the 200ml ether mixture of-78 ℃ 2.16g pyridine and 6.3ml t-butyldimethylsilyl triflate.Allow reactant mixture go back up to room temperature, stirring is spent the night.Make reaction terminating with 75ml water, aerating oxygen 3 hours.Reactant mixture dilutes until pH=1 with ether and 3N HCl, separates organic layer then.Water layer until pH=8~9, is used chloroform (3 * 100ml) extractions with the 20%NaOH alkalization then.Na is used in organic layer water, saline (200ml) washing
2SO
4Drying, filtration and evaporation.
To the 100ml of 3.42g above-claimed cpd CHCl
3Add the 30g activated manganese dioxide in the solution, stirring is spent the night.Solid is leached the filtrate evaporation with diatomite layer.
Do the THF solution that adds 16.3ml hexamethyl two silicon Hydrazoic acid,sodium salt in the THF solution at 0 ℃ of 30ml, stirred 30 minutes to 2.4ml triethylphosphine acetate.Add the 10mlTHF solution of above-mentioned aldehyde intermediate, stirred 30 minutes, with the saturated NH of 25ml
4Cl solution makes reaction terminating, with EtOAc (3 * 25ml) extractions.Na is used in the organic layer salt water washing that merges
2SO
4Drying concentrates.Residue is that eluant dodges anxious chromatography purification with hexane-EtOAc (4: 1), provides 1.5g faint yellow solid shape expection product.
1H?NMR(CDCl
3,400MHz)d8.63(d,2H),7.68(dd,1H),7.60(d,1H),7.45-7.35(m,2H),7.30(dd,1H),7.35(d,1H),4.15(q,2H),1.23(t,3H).
In the 25ml of the above-mentioned intermediate of 1.5g methanol solution, add the EtOAc solution of 5ml 4M HCl, be evaporated to dried.This solid is dissolved in the 30ml methanol, adds 0.50g PtO
2, 50psi hydrogenation 5 hours.With diatomite layer catalyst is leached, filtrate concentrates, and provides title compound.
1H NMR shows that this material contains the 5% cyclohexyl piperidines of having an appointment.
1H?NMR(CD
3OD,400MHz)d?7.40-7.20(m,4H),4.08(q,2H),3.50(m,2H),3.25-3.10(m,3H),3.00(t,2H),2.60(t,2H),2.03-1.90(m,4H),1.20(t,3H).
Step C:
To above-mentioned intermediate and 30ml CH
2Cl
2Mixture in add 0.82ml triethylamine, 1.2ml NMM, (its preparation sees people J.Am.Chem.Soc. such as H.K.Chenault for details to 0.90g HOBT, 2.13g (2R)-N-tBOC-5-phenylpentanoic acid, 111,6354-6364 (1989)), adds 1.7g EDC at last, stirring at room 18 hours.The saturated NaHCO of reactant mixture impouring
3In the solution, use CH
2Cl
2Extraction.The organic layer that merges is used Na with 0.1N HCl, salt water washing
2SO
4Drying concentrates.
More than thick material dissolution at 30ml CH
2Cl
2In, add 10ml TFA, stirring at room 1 hour.Make solvent evaporation to doing residue Na
2CO
3CH is used in the aqueous solution neutralization
2Cl
2Extraction.K is used in the organic layer salt water washing that merges
2CO
3Drying concentrates.To this intermediate and 30ml CH
2Cl
2Mixture in add 1.04g HOBT, 1.56gN-tBOC-Alpha-Methyl alanine, add 1.8g EDC at last, stirring at room 4 hours.The saturated NaHCO of reactant mixture impouring
3Solution is used CH
2Cl
2Extraction.The organic layer that merges is used MgSO with 0.1N HCl, salt water washing
4Drying concentrates.The oily residue is with CH
2Cl
2-acetone-ether (6: 1: 1) provides the expection material for the anxious chromatography purification of the sudden strain of a muscle of eluant.
1H?NMR(CDCl
3,400MHz)d?7.30-6.98(m,9H),5.00-4.85(m,2H),4.72-4.64(m,1H),4.13(2q,2H),4.00-3.82(m,1H),3.14-2.85(m,4H),2.7-2.50(m,5H),1.83-1.50(m,5H),1.50(s,3H),1.46(s,1.5H),1.44(s,1.5H),1.40(s,9H),1.40-1.28(m,1H),1.23(2t,3H).
The 30ml CH of the intermediate that obtains to 1.70g step C
2Cl
2Add 10mlTFA in the solution, stirring at room 1 hour.Reactant mixture is evaporated to dried, uses Na
2CO
3CH is used in the aqueous solution alkalization
2Cl
2Extraction.K is used in the organic layer salt water washing that merges
2CO
3Drying is filtered, is evaporated, and provides viscous crude shape free alkali.This material dissolution adds the EtOAc solution of 0.5ml 4M HCl in 0 ℃ 5ml ether.Precipitate is at N
2Filter under the atmosphere, drying provides title compound.
1H?NMR(CD
3OD,400MHz)d?7.30-6.98(m,9H),5.00-4.85(m,2H),4.72-4.64(m,1H),4.13(2q,2H),4.00-3.82(m,1H),3.14-2.85(m,4H),2.7-2.50(m,5H),1.83-1.50(m,5H),1.50(s,3H),1.46(s,1.5H),1.44(s,1.5H),1.40-1.28(m,1H),1.23(2t,3H).
Example B2
Steps A:
In the 5ml anhydrous THF solution of the intermediate that 0.20g example B1 step C obtains, add 46mg trimethyl silyl potassium alcoholate.Add 46mg trimethyl silyl potassium alcoholate and 2ml THF after 2 hours again, in stirred overnight at room temperature.Reactant mixture is with the dilution of 10ml water, with ether (2 * 10ml) washings.Water layer is acidified to pH=2 with 0.1N HCl, uses CH
2Cl
2(2 * 15ml) extractions.Na is used in the organic layer salt water washing that merges
2SO
4Dry, filtration, concentrated.Residue is with CHCl
3-MeOH-NH
3OH (85: 15: 1) provides 56mg expection material for the anxious chromatography purification of the sudden strain of a muscle of eluant.
1H?NMR(CDCl
3,400MHz)d7.32-7.20(m,4H),7.20-6.98(m,5H),5.10(bs,1H),5.00-4.90(m,1H),4.65(bt,1H),4.90(dd,1H),3.10-2,85(m,4H),2.70-2.50(m,5H),1.80-1.50(m,5H),1.50(s,4H),1.46(s,1H),1.42(s,1H),1.38(s,9H),1.35-1.20(m,1H).
Step B:
At the EtOAc solution of room temperature, kept 2 hours in room temperature to above-mentioned intermediate interpolation 2ml 4M HCl.Reactant mixture is evaporated to dried, and residue is developed with ether, provides the white solid title compound.
1H?NMR(CD
3OD,400MHz)d?8.15(t,1H),7.30-7.00(m,9H),4.90(m,1H),4.60(bd,1H),4.05(d,1/2H),3.95(d,1/2H),3.25-3.05(m,2H),3.00(dt.2H),2.80-2.50(m,5H),1.85-1.63(m,6H),1.63(s,2H),1.60(s,4H),1.60-1.20(m,2H).
This title compound prepares described in example B1 step C and D, but replaces (R)-2-N-t-BOC-5-phenylpentanoic acid with the commercial N-t-BOC-O-benzyl that gets-D-serine.
1H?NMR(CD
3OD,400MHz)d?8.30(d,1/2H),8.23(d,1/2H),7.40-7.25(m,5H),7.20-7.05(m,3.5H),6.88(d,1/2H),5.20(m,1H),4.70-4.50(m,3H),4.20-4.05(m,3H),3.84-3.65(m,2H),3.28-2.95?9m,4H),2.75(q,1H),2.58(dt,2H),1.85-1.70(m,2H),1.64(s,2H),1.61(s,4H),1.55-1.40(m,2H),1.20(2t,3H).
In the chemical compound of 54mg example B3 preparation, add 2ml 2N HCl aqueous solution, in stirred overnight at room temperature.Remove solvent under the decompression, the residue vacuum drying provides title compound.
1H?NMR(CD
3OD,400MHz)d?8.30(d,1/2H),8.23(d,1/2H),7.40-7.25(m,5H),7.20-7.05(m,3.5H),6.88(d,1/2H),5.20(m,1H),4.70-4.50(m,3H),4.20-4.05(m,1H),3.84-3.65(m,2H),3.28-2.95(m,4H),2.75(q,1H),2.58(dt,2H),1.85-1.70(m,2H),1.64(s,2H),1.61(s,4H),1.55-1.40(m,2H).
Example B5
The 3ml CH of the intermediate that obtains to 0.109g example B2 steps A
2Cl
2Add 0.017ml ethanolamine, 34mg HOBT and 58mg EDC in the solution, in stirred overnight at room temperature.Reactant mixture 10ml CH
2Cl
2Dilution is with 5ml 0.10N HCl, the saturated NaHCO of 5ml
3Solution washing is used MgSO
4Dry, concentrated.Residue is with CH
2Cl
2-acetone (3: 2) is the anxious chromatography purification of the sudden strain of a muscle of eluant, provides a pair of product.
The same with the front, above-mentioned material is at room temperature CH
2Cl
2-TFA handled 30 minutes, was evaporated to driedly, developed with ether, provided faint yellow solid shape title compound.
1H?NMR(CD
3OD,400MHz)d?8.15(t,1H),7.30-7.00(m,9H),4.95(m,1H),4.60(bd,1H),4.40(bs,1H),4.00(bdd,1H),3.60-3.50(m,2H),3.40-3.10(m,4H),3.05-2.90(m,2H),2.85-2.60(m,5H),2.52-2.40(m,4H),1.90-1.65(m,6H),1.63(s,2H),1.60(s,4H),1.60-1.20(m,2H).
Example B6
In 9.0g 2-bromobenzene ethanol 6.12ml dihydropyran solution, add 2 concentrated hydrochloric acid in room temperature, stirring at room 1 hour.Reactant mixture is used saturated NaHCO with the dilution of 150ml ether
3(2 * 100ml), saline (150ml) washing, use MgSO
4Drying concentrates, and provides a kind of thick grease.Residue is the eluant anxious chromatography purification of sudden strain of a muscle with hexane-EtOAc, provides 10g ether.
In the 200ml dry diethyl ether, add 17.7ml 1.6M nBuLi hexane solution at-78 ℃.In this solution, add the 100ml THP trtrahydropyranyl ethereal solution of 8.0g ether intermediate, stirred 30 minutes ,-40 ℃ of restir 30 minutes at-78 ℃.This solution in the dropping mode in-78 ℃ of 200ml ether mixture that add 2.16g pyridine and 6.3ml t-butyldimethylsilyl triflate to.Allow reactant mixture go up to room temperature, stirring is spent the night.Reaction stops with 75ml water, aerating oxygen 3 hours.Reactant mixture dilutes until pH=1 with ether and 3N HCl, separates organic layer then.Water layer until pH=8~9, is used chloroform (3 * 100ml) extractions with 20% NaOH alkalization then.Na is used in organic layer water, saline (200ml) washing
2SO
4Drying, filtration, evaporation.Residue is the anxious chromatography purification of sudden strain of a muscle of eluant with hexane-ethyl acetate (1: 1), provides the expection product.
Approximately 0.90g with 4M HClEtOAc solution-treated, makes it to change into hydrochlorate by the phenyl-pyridine intermediate of the above method preparation.
1H?NMR(CDCl
3,400MHz)d?8.90(d,2H),8.20(dd,1H),7.73-7.35(m,4H),3.70(t,2H),2.83(t,2H).
Step B:
In the 25ml of the above-mentioned intermediate of 0.90g methanol solution, add 0.10g PtO
2, be the hydrogen hydrogenation 5 hours of 50psi with pressure.Catalyst is leached, and filtrate concentrates.Residue was handled 18 hours with 1.4g dimethyl dicarbonate butyl ester in 3ml diox, 1ml water and 1ml triethylamine.Protected piperidines is with CH
2Cl
2-acetone (10: 1) separates with dodging anxious chromatography as eluant.
More than 0.25g, add 2ml CH in the synthetic protected piperidines intermediate
2Cl
2With 0.50ml TFA, stirring at room 30 minutes.Reactant mixture is evaporated to dried, with methylbenzene azeotropic.
To the 2ml of above residue CH
2Cl
2Add 0.079g HOBT, 0.14g intermediate 2,0.070ml NMM and 0.090g EDC in the solution, in stirred overnight at room temperature.The saturated NaHCO of reactant mixture impouring
3In the solution, use CH
2Cl
2Extraction.The organic layer that merges is used MgSO with 0.5NHCl, salt water washing
4Dry, concentrated.Residue is with CH
2Cl
2-acetone (9: 1) is the anxious chromatography purification of the sudden strain of a muscle of eluant, provides a pair of product.
The deprotection of uncle's N-fourth oxygen phosphinylidyne group is at 2ml CH
2Cl
2In processing was carried out in 2 hours to above-mentioned intermediate with 1ml TFA.Reactant mixture concentrates, with ether development, vacuum drying, provide colorless solid shape title compound.
1H?NMR(CD
3OD,400MHz)d?7.40-6.88(m,9H),5.17(bs,1H),4.77-4.50(m,3H),4.18(bd,1H),3.80-3.65(m,4H),3.30-3.05(m,4H),2.95-2.70(m,2H),1.85-1.60(m,2H),1.60(s,2H),1.58(s,4H),1.70-1.45(m,2H).
Steps A:
The PtO of the phenyl for preparing in the example B1 steps A-piperidines intermediate
2Reduction in different solvents such as ethanol and methanol, is having and is not having in the presence of the dense HCl and attempt.Observe the non-selective reduction of transesterification and pyridine.These reactions have several the combination, and at CH
2Cl
2With handle with excessive dimethyl dicarbonate ester in the triethylamine.The about 5.0g roughage that obtains after sour post processing was in this way handled 2 hours with 1.6g NaOH in 100ml methanol and 10ml water.The reactant mixture dilute with water washs with ether.Water layer until being acid, is used CHCl with 0.50N HCl acidify
3Extraction.Na is used in the organic layer salt water washing that merges
2SO
4Dry, filtration, concentrated.At the 150ml CH of room temperature to this nipecotic acid of about 4.0g
2Cl
2Add 1.86ml benzylalcohol, 1.90g HOBT, 3.45g EDC and catalytic amount DMAP in the solution, in stirred overnight at room temperature.The saturated NaHCO of reactant mixture
3, 0.50N HCl, salt water washing, use Na
2SO
4Drying is filtered and is concentrated.With obtaining expecting material after dodging anxious chromatography purification.
1H?NMR(CDCl
3,400MHz)d?7.40-7.28(m,5H),7.22-7.10(m,4H),5.12(s,2H),4.25(bs,2H),3.04(t,2H),2.94-2.70(m,3H),2.67?9t,2H),1.75-1.60(m,3H),1.53(s,9H),1.33-1.20(m,1H).
To the 2.5ml of the above-mentioned intermediate of 0.70g CH
2Cl
2Add 1ml TFA in the solution, reactant mixture was stirring at room 1 hour.Reactant mixture is evaporated to dried, is dissolved in saturated NaHCO
3In the aqueous solution, use CH
2Cl
2Extraction.K is used in the organic layer salt water washing that merges
2CO
3Drying concentrates.Residue and intermediate 1 react described in example B6 step B.Residue is the anxious chromatography purification of sudden strain of a muscle of eluant with hexane-acetone-ether (6: 1: 1), provides 0.47g expection material.
Step C:
In the EtOAc of the above-mentioned intermediate of 0.20g solution, feed HCl gas about 10 seconds at 0 ℃.Reactant mixture was added a cover, is stirred 30 minutes.Add ether, precipitate is at N
2Filter under the atmosphere.This provides 0.195g white solid title compound.NMR points out 2: 1 mixture of rotamer.
1H NMR (CD
3OD, 400MHz) d 8.30 and 8.20 (2d, 1H), 7.53 and 7.45 (2d, 1H), 7.40 and 7.35 (2d, 1H), 7.30-7.00 (m, 11 and 1/3), 6.54 (d, 2/3H), 5.30-5.18 (m, 1H), 5.09 and 5.05 (2s, 2H), 4.60 and 4.55 (2d, 1H), 3.90 (2d, 1H), 3.35 (dd, 1H), 3.20 (dd, 1H), 3.00-2.85 (m, 3H), 2.75-2.40 (4H), 1.64 (s, 6H), 1.40 (d, 2/3H), 1.06 (d, 2/3H), 0.73 (dt, 1/3H) ,-0.03 (dt, 1/3H).
Example B8
In the 3ml dioxane solution of the intermediate that 0.19g example B7 step C obtains, add 50mg 10%Pd/C, at H
2Hydrogenation is 3 hours under the atmosphere.Reaction is so slow, thereby adds about 50mg 20%Pd (OH) again
2/ C, hydrogenation spends the night.Catalyst leaches with diatomite layer, and the Yong diox washs.The filtrate evaporation provides pink solid shape title compound.
NMR points out 2: 1 mixture of rotamer.
1H NMR (CD
3OD, 400MHz) d 8.30 and 8.20 (2d, 1H), 7.53 and 7.45 (2d, 1H), 7.40 and 7.35 (2d, 1H), 7.20-7.00 (m, 6 and 1/3), 6.54 (d, 2/3H), 5.30-5.18 (m, 1H), 4.60 and 4.55 (2d, 1H), 3.90 (2d, 1H), 3.35 (dd, 1H), 3.20 (dd, 1H), 3.00-2.85 (m, 3H), 2.75-2.40 (4H), 1.64 (s, 6H), 1.40 (d, 2/3H), 1.06 (d, 2/3H), 0.73 (dt, 1/3H) ,-0.03 (dt, 1/3H).
In the synthetic benzylalcohol-pyridine intermediate of 0.20g example B1 steps A, add 2ml dry acetone and 0.10ml benzyl bromide a-bromotoluene, stirring at room 1 hour.On rotary evaporator, remove volatile matter, residue and methylbenzene azeotropic.Residue is dissolved in the methanol, handles 1 hour with the 0.10g sodium borohydride.The reactant mixture dilute with water is used CH
2Cl
2Extraction.The organic layer salt water washing that merges is with dried over mgso, filtration, evaporation.This provides the mixture of N-benzyl tetrahydro pyridine, and the latter is catalyst hydrogenation 5 hours with 10%Pd/C in ethanol.Catalyst leaches, and filtrate concentrates.Residue is with CH
2Cl
2-methanol (90: 10) provides the mixture of 70mg tetrahydropyridine and hexahydropyridine for eluant carries out purification.To the 5ml of 70mg said mixture CH
2Cl
2Add 0.10g intermediate 3,0.040g HOBT and 0.070gEDC in the solution, in stirred overnight at room temperature.The saturated NaHCO of reactant mixture impouring
3In the aqueous solution, use CH
2Cl
2Extraction.Na is used in the organic layer salt water washing that merges
2SO
4Drying concentrates.Residue is the anxious chromatography purification of sudden strain of a muscle of eluant in order to hexane-EtOAc (4: 1), provides a pair of product of 0.090g, is the non-enantiomer mixture form.
Above-mentioned a pair of product is catalyst hydrogenation 18 hours with 10% Pd/C in ethanol.Catalyst leaches with one deck kieselguhr, and filtrate concentrates.Residue is with CH
2Cl
2-ether (6: 1) is the anxious chromatography purification of the sudden strain of a muscle of eluant, provides 90mg expection product.
The last deprotection of above-mentioned intermediate is to carry out 5 hours in the presence of the dense HCl of 1ml in methanol (2ml).Reactant mixture is evaporated to dried, and residue is developed with ether, provides a kind of solid.This material LH
20Post is the MPLC purification of eluant with methanol, provides 34mg white solid title compound.
1H?NMR(CD
3OD,400MHz)d?7.35-7.04(m,9H),4.95(m,1H),4.69(d,2H),4.60(d,1H),3.97(dd,1H),3.30-3.10?9m,3H),2.82-2.60?9m,4H),1.90-1.70(m,5H),1.63?9s,2H),1.60(s,4H),1.55-1.40(m,1H).
The intermediate (930mg, the mixture of two kinds of diastereomers) of example B12 step B preparation is dissolved in the methanol, with atmospheric pressure Pd (OH)
2Hydrogenation 12 hours.The mixture diatomite filtration, the filtrate vacuum concentration provides the protected product of 700mg.In the 0.5ml dichloromethane solution of this residue (5.5mg), add N-BOC-(D)-alanine (4.9mg), EDC (5.0mg) and HOBT (3.5mg).After stirring is spent the night, in the mixture impouring water, use dichloromethane extraction, use the salt water washing.Organic layer dried over sodium sulfate, filtration, concentrated.Residue provides a pair of product with PLC (hexane/ethyl acetate=1/1) purification.The final deprotection of this coupling intermediate carries out according to step described in the example B19 step B, provides the 7.8mg expecting compound.
1H NMR (400MHz, CD
3Cl, the mixture of diastereomer and rotamer): 7.59 (m, 1H), 7.39-7.01 (m, 9H), 5.37 (m, 1/2H), 5.18 (m, 1/2H), 4.61 (m, 1H), 4.30 (m, 1/2H), 4.02-3.61 (m, 3H), (3.35-2.35 m, 7 1/2H), 1.60 (m, 1H), (1.56 d, 7Hz 3/2H), 1.50 (m, 3/2H), 0.95 (m, 3/2H), 0.88 (m, 3/2H) .FAB-MS:491.0 (M+1).
Example B11
In the 2ml chloroformic solution of the chemical compound of 0.10g example B15 steps A preparation, add 0.018g 5-amino methyl tetrazolium, 0.027g HOBT, 0.65ml triethylamine and 0.048g EDC at 0 ℃, stirred 10 minutes at 0 ℃.Add 1ml DMF in this suspension, stirring is spent the night.Reactant mixture concentrates, and residue uses preparation type TLC (1mm plate) with CHCl
3-MeOH-NH
4OH (90: 10: 1) provides the expection material for eluant separates.FAB-MS m/e value of calculation C
34H
46N
8O
5643,36; Measured value 647.2 (m+1).
In the 1ml of the above-mentioned product of 0.025g ethyl acetate cooling solution, feed HCl (gas), make it to leave standstill 30 minutes in room temperature until reaching capacity.Reactant mixture concentrates, and provides title compound.
1H NMR (200MHz:CD
3OD) point out the rotamer mixture: 7.91 (d, J=8Hz); 7.35-7.06 (m); 5.14 (bs); 4.65-4.48 (m); 3.92 (bt, J=13); 3.72-3.04 (m); 2.76-2.58 (m); 1.95-1.68 (m); 1.61 (s); 1.28 (s) .FAB MS value of calculation C
34H
46N
8O
5: MW=546.31; Measured value m/e=(m+1) 547.1.
(11.4g 54.9mmole) in the solution in 82ml 1N sodium hydrate aqueous solution, at room temperature adds dimethyl dicarbonate butyl ester (12.2g, 82ml dioxane solution 56.0mmole) to 3-ethoxy phosphinylidyne-4-piperidone hydrochloride.After 12 hours, mixture dilutes with ethyl acetate, with 0.5N hydrochloric acid and salt water washing.Organic layer dried over mgso, filtration, concentrated.At-78 ℃, in the 200ml of thick residue dichloromethane, add diisopropylethylamine (14.3ml, 82.3mmole) and the triflic acid anhydride (10.1ml, 60.4mmole).After 12 hours, in the mixture impouring saturated sodium bicarbonate solution, use dichloromethane extraction.Organic layer is used dried over mgso with 1N hydrochloric acid, salt water washing.Organic layer concentrates, and provides triflic vinyl acetate (21.0g, 95%).At room temperature to the triflic vinyl acetate (4.67g, add in 100ml dichloromethane 116mmole) and the 100ml 1-Methyl-2-Pyrrolidone solution phenyl tin trimethyl (2.1ml, 11.6mmole) and acid chloride (0.13g, 0.58mmole).After a few hours, in the reactant mixture impouring water, with extracted with diethyl ether (3 times).Dried over mgso is used in organic layer water (3 times), salt water washing.Concentrate and purification (MPLC, hexane/ethyl acetate=10/1), isolate expecting compound (83% productive rate, 3.2g).
Steps A:
(3.2g, 9.66mmole) preparation is dissolved in it in 100ml methanol the intermediate that obtains from steps A-1, uses PtO under an atmospheric pressure
2Hydrogenation a few hours (reacting very slow) adds a Pd/C then again under hydrogen.Mixture stirred 72 hours, used diatomite filtration then.The filtrate vacuum concentration.Residue provides cis-compound (1.9g) with MPLC (hexane/ethyl acetate=10/1) purification.
Intermediate (200mg, 0.6mmole) the middle 2ml TFA that adds to the steps A preparation.After 10 minutes, mixture concentrates, and with toluene (3 times) azeotropic, residue is dissolved in the ethyl acetate, washs with sodium bicarbonate.Organic layer concentrates.In the 10ml of residue dichloromethane solution, add the N-CBZ-D-tryptophan (223mg, 0.66mmole), EDC (138mg, 0.72mmole) and HOBT (89mg, 0.66mmole).After a few hours, in the reactant mixture impouring water, use dichloromethane extraction, with dried over sodium sulfate, filtration, concentrated.Residue provides two kinds of diastereomers with MPLC (hexane/ethyl acetate=2/1) purification, and gross production rate is 66% (the diastereomer d that polarity is more weak
1, 82mg; And the stronger diastereomer d of polarity
2, 138mg).
The more weak diastereomer (82mg) of step B Semi-polarity is dissolved in the 5ml methanol, under-atmospheric pressure with Pd/C hydrogenation a few hours (monitoring) with TLC.The mixture diatomite filtration, the filtrate vacuum concentration.In the 5ml of residue chloroformic solution, add N-CBZ-Alpha-Methyl alanine (38mg), EDC (31mg) and HOBT (21mg).After 3 hours, in the mixture impouring water, use dichloromethane extraction in stirring at room, use the salt water washing.Organic layer dried over sodium sulfate, filtration, concentrated.Residue provides expecting compound (60mg) with chromatatron (hexane/ethyl acetate=1/1) purification with 69% productive rate.
The intermediate that step C obtains is dissolved in the 3ml methanol, uses Pd (OH) under an atmospheric pressure
2/ C hydrogenation one hour (monitoring) with TLC.The mixture diatomite filtration, the filtrate vacuum concentration.Residue is used the HCl acidify in ether, provide a kind of white depositions (d
1, 40mg).
1H NMR (400MHz, CD
3OD rotamer mixture): 7.64 (d, 8Hz, 1/2H), 7.57 (d, 8Hz, 1/2H), 7.37-7.01 (m, 9H), 5.28 (dd, 8,5Hz, 1/2H), 5.18 (t, 7Hz, 1/2H), 4.76 (m, 1H), 4.30 (m, 1/2H), 4.15 (m, 1/2H), 3.81 (m, 2 1/2H), 3.35 (m, 1/2H), 3.16 (m, 2 1/2H), 3.02 (m, 1 1/2H), 2.98 (m, 1/2H), 2.45 (m, 1H), 2.25 (m, 1/2H), 1.74 (m, 1/2H), 1.63 (m, 1/2H), 1.57 (s, 3/2H), 1.52 (s, 3/2H), 1.49 (s, 3/2H), 1.34 (s, 3/2H), 0.98 (t, 7Hz, 3/2H), 0.90 (t, 7Hz, 3/2H) .FAB-MS:505.6 (M+1).
According to step described in example B12 step C and the D, use intermediate (93mg) preparation that obtains from the stronger diastereomer of polarity of example B12 step B, provide expecting compound (d
2, 56mg).
1H NMR (400MHz, CDCl
3, the rotamer mixture): 7.57 (m, 1H), 7.35-6.94 (m, 9H), 5.37 (t, 7Hz, 2/3H), 5.17 (m, 1/3H), 4.61 (m, 1H), 4.28 (m, 1/3H), 4.06 (m, 2/3H), 3.84-3.53 (m, 2H), 3.28-2.80 (M, 5H), 2.53 (M, 1H), 1.61 (S, 2H), 1.51 (S, 1H), 1.47 (S, 2H), 1.29 (S, 1H), 0.95 (t, 7Hz, 2H), 0.80 (t, 7Hz, 1H) .FAB-MS:505.7.
Example B14 (trans, d
1+ d
2)
The small pieces sodium metal is added in the 2.5ml dehydrated alcohol.When sodium dissolved, the intermediate (40mg) that example B12 steps A is obtained added in the reactant mixture, and placed 2 hours in 80 ℃ of oil baths.Among this mixture impouring 0.1N HCl, use extracted with diethyl ether.Organic layer dried over sodium sulfate, filtration and concentrated.Residue provides transisomer (26mg) with PLC (hexane/ethyl acetate=5/1) purification.
Intermediate (24mg) and intermediate 1 with steps A obtains according to the preparation of the step described in example B7 step B and the C, provide the product of 5.4mg hydrochloride form.
1H NMR (400MHz, CD
3OD, the mixture of diastereomer and rotamer): 7.63-7.35 (m, 2H), 7.24-6.75 (m, 8H), 5.01 (m, 1H), 4.60 (m, 1H), 4.08-3.68 (m, 3 1/3H), 3.39-2.41 (m, 5 2/3H), 1.78-0.96 (1 1/3H), 1.62 (s, 3H), 1.61 (s, 3H), 0.86 (m, 3H), 0.66 (m, 1/3H) ,-0.10 (m, 1/3H) .FAB-MS:505.6 (M+1).
Approximately piperidines intermediate and 0.39g intermediate 3,0.152g HOBT, 0.17ml N-methylmorpholine and the 0.225g EDC of the preparation of 0.250g example B44 steps A reacted 18 hours in the 15ml chloroform.Reactant mixture 0.50N HCl (10ml), saturated NaHCO
3Aqueous solution (10ml) washs, uses MgSO
4Dry, concentrated.Crude product is the anxious chromatography purification of sudden strain of a muscle of eluant in order to hexane-EtOAc (4: 1).
In mixture solution add 25ml Lithium hydrate at 1: 1 to the 10ml of this material of 0.136g methanol-water, stirring is spent the night.Reactant mixture washes with water with the dilution of 10ml water, and water layer is acidified to pH=2 with 0.50N HCl, with ether (3 * 10ml) extractions, the organic layer of merging with the salt water washing, use MgSO
4Dry, concentrated, provide white solid expection material.
Title compound is the compound of making from steps A, promptly in room temperature with saturated HCl (gas) ethyl acetate solution to its processing 30 minutes.Add ether, with precipitation leach, drying.
1H NMR (400MHz, CD
3OD rotamer mixture): 8.10 (t, 1H), 7.78 (dd, 1H), 7.50-7.00 (m, 8H), 4.90 (m, 1H), 4.55 (d, 1H), 3.94 and 3.90 (2doublets, 1H), 3.80-3.60 (m, 1H), 3.05 (dt, 1H), 2.70-2.50 (m, 4H), 1.90-1.50 (m, 6H), 1.55 (s, 3H), 1.50 (s, 3H), 1.40 (m, 1H).
Example B16
Steps A:
-78 ℃ of intermediate that obtain to example B12 steps A (89mg, add in 2ml THF solution 0.267mmole) two (trimethyl silyl) ammonification potassium (0.5M, 800ml, 0.4mmole).After 1/2 hour, in reactant mixture, add methyl iodide (22ml, 0.34mmole).This reactant mixture slowly gos up to room temperature, restir 12 hours.In the mixture impouring water, use extracted with diethyl ether then.Organic layer dried over sodium sulfate, filtration, concentrated.Residue provides expecting compound (91mg, 98%) with chromatatron (hexane/ethyl acetate=1/1) purification.
Intermediate (91mg) with steps A obtains according to the preparation of the step described in example B12 step B, C and the D, provides expecting compound.
1H NMR (400MHz, CD
3OD, the mixture of diastereomer and rotamer): 7.58 (m, 1H), 7.37-7.00 (m, 9H), 5.40-5.23 (m, 1H), 4.60 (m, 1H), 4.20-3.73 (m, 3H), 3.40 (m, 1/2H), 3.15 (m, 2H), 2.82 (m, 1H), (2.61-2.30 m, 2 1/2H), 1.72 (m, 1/2H), 1.63-1.29 (m, 6H), 1.13-0.84 (m, 6H) .EI-MS:518.2 (M).
Example B17 (cis, d
1+ d
2)
Under agitation, (1.0g adds 4N sodium hydroxide (4ml) to the intermediate for preparing to example B12 steps A-1 in 4ml alcoholic solution 3.02mmole).Reactant mixture is in stirring at room 16 hours, vacuum evaporation.The residue dilute with water is used the 0.5N hcl acidifying, uses extracted with diethyl ether then.Organic layer dried over sodium sulfate, filtration, concentrated.Thick residue is dissolved in the methanol, uses Pd (OH) under an atmospheric pressure
2Hydrogenation 16 hours.The mixture diatomite filtration, the filtrate vacuum concentration.In the 10ml of this thick acid chloroformic solution, add benzylalcohol (341ml), EDC (750mg) and catalytic amount DMAP.After 16 hours, mixture dilutes with dichloromethane, then water and salt water washing.Organic layer dried over mgso, filtration, concentrated.Residue provides expecting compound (459mg, 38%) with MPLC (hexane/ethyl acetate=5/1) purification.
Step B:
At intermediate (459mg, 1.16mmole) middle the add 2mlTFA of room temperature to the steps A preparation.After 10 minutes, reactant mixture concentrates, with toluene (3 times) azeotropic.In the 10ml of residue chloroformic solution, add intermediate 1 (433mg), EDC (265mg), HOBT (172mg) and triethylamine (194ml).Reactant mixture is stirring at room 3 hours, in the impouring water.The mixture dichloromethane extraction is used dried over sodium sulfate.Concentrated and purification (MPLC, hexane/ethyl acetate=1.5/1) provides a pair of product (574mg), and productive rate is 76%.
In the intermediate (10mg) that step B obtains, add TFA in room temperature.After 10 minutes mixture is concentrated, provide expecting compound (3mg).
1H NMR (400MHz, CD
3OD, the mixture of diastereomer and rotamer): 7.62 (m, 1H), 7.37-6.81 (m, 14H), 5.42-5.15 (m 1H), 4.79 (m, 2H), 4.65 (m, 1H), 4.32 (m, 1/2H), 4.12 (m, 1/2H), 3.27-2.85 (m, 5 1/2H), (2.55-2.27 m, 1 1/2H), 1.74 (m, 1H), 1.60-1.29 (m, 6H) .FAB-MS:567.0 (M+1).
Example B18 (cis, d
1+ d
2)
Intermediate (20mg) with example B17 step B obtains according to the preparation of step described in the example B8, provides expecting compound.
Step B:
Intermediate with steps A obtains according to the preparation of step described in the example B17 step C, provides expecting compound (10mg).
1H NMR (400MHz, CD
3OD, the mixture of diastereomer and rotamer): 7.62 (m, 1H), 7.37-6.98 (m, 9H), 5.36-5.21 (m1H), 4.69 (m, 1/2H), 4.58 (m, 1/2H), 4.27-3.91 (m, 2H), and 3.27-2.75 (m, 5H), 2.51-2.34 (m, 2H), 1.72 (m, 1H), 1.58-1.21 (m, 6H) .FAB-MS:576.9 (M+1).
Its preparation is that the intermediate (142mg) that obtains with example B18 steps A is in the 3ml dichloromethane, to wherein adding 2-(methyl mercapto) ethanol (22ml), EDC (57mg) and catalytic amount DMAP.After 3 hours, mixture dilutes with dichloromethane, then water and salt water washing.Organic layer dried over mgso, filtration, concentrated.Residue provides expection product (69mg, 43%) with PLC (hexane/ethyl acetate=1/1).
Step B:
Its preparation be the intermediate (50mg) that obtains with steps A in the 2ml ether, at 0 ℃ to wherein feeding HCl gas.After 30 seconds, mixture concentrates, and provides white solid (41mg).
1H NMR (400MHz, CD
3OD, the mixture of diastereomer and rotamer): 7.61 (m, 1H), 7.37-6.97 (m, 9H), 5.38-5.18 (m 1H), 4.83-4.54 (m, 1H), 4.37-3.77 (m, 3H), 3.57-2.83 (m, 6H), and 2.55-2.21 (m, 3H), 2.14-1.84 (m, 3H), 1.72 (m, 1H), 1.61-1.29 (m, 6H) .FAB-MS:551.0 (M+1).
Its preparation is that the intermediate (52mg) that obtains with example B18 steps A is in the 3ml dichloromethane, to wherein adding ethylamine hydrochloride (9mg), EDC (21mg), triethylamine (15ml) and catalytic amount DMAP.After 3 hours, mixture dilutes with dichloromethane, then water and salt water washing.Organic layer dried over mgso, filtration, concentrated.Residue provides a pair of product (25mg) with PLC (methylene chloride=20/1) purification.This intermediate provides expecting compound (25mg) according to the step process of describing among the example B17 step C.
1H NMR (400MHz, CD
3OD, the mixture of diastereomer and rotamer): 7.68-6.93 (m, 10H), 5.34-5.12 (m 1H), 4.75-4.30 (m, 2H), 3.50-2.60 (m, 8H), 1.72-1.17 (m, 8H), 0.83-0.68 (m, 3H) .FAB-MS:504.0 (M+1).
Example B21 (cis, d
1+ d
2)
(950mg, (1.0N dichloromethane solution, 8ml 8.0mmole), carry out at-78 ℃ the intermediate that obtains to example B12 steps A-1 to add diisobutylaluminium hydride in 10ml THF solution 2.87mmole).Mixture stirred 1 hour at 0 ℃, slowly went up to room temperature then.Mixture is with 1N sodium hydroxide cessation reaction, with ether (3 times) extraction.Organic layer dried over sodium sulfate, filtration, concentrated.Residue provides the 617mg reduzate with MPLC (hexane/ethyl acetate=2/1) purification.
Step B:
Its preparation is intermediate (57mg) hydrogenation under condition described in the example B12 steps A that obtains with steps A, provides expecting compound (13mg).
Step C:
Intermediate (13mg) with step B obtains according to the preparation of step described in example B17 step B and the C, provides expecting compound (12mg).
1H NMR (400MHz, CD
3OD, the mixture of diastereomer and rotamer): 7.74-6.80 (m, 10H), 5.55 (m 1/2H), 5.20 (m, 1/2H), 4.66 (m, 1H), 4.11 (m, 1/2H), 3.93 (m, 1/2H), 3.20 (m, 3H), 3.00-2.82 (m, 2 1/2H), 2.69-2.45 (m, 2 1/2H), 2.05-1.84 (m, 1H), 1.68 (s, 3/2H), 1.61 (s, 3/2H), 1.60 (s, 3/2H), 1.47 (s, 3/2H), 0.90 (m, 1/2H), 0.17 (m, 1/2H) .FAB-MS:463.0 (M+1).
Example B22 (cis, d
1+ d
2)
Its preparation is that (330mg 1.14mmole) in the 10ml dichloromethane, to wherein adding acetic anhydride (130mg), triethylamine (240ml) and catalytic amount DMAP, carries out at 0 ℃ the intermediate that obtains with example B21 steps A.After 1 hour, in this mixture, add water, at room temperature it was stirred 1 hour again.The mixture dichloromethane extraction is used 1 N sodium hydroxide and salt water washing then successively.Organic layer dried over mgso, filtration, concentrated.Residue is hydrogenation under condition described in the example B12 steps A, provides expecting compound.
Step B:
The intermediate (24mg) that obtains with steps A prepares according to example B17 step B and the described step of example B19 step B, provides expecting compound (23mg).
1H NMR (400MHz, CD
3OD, the mixture of diastereomer and rotamer): 7.74-6.87 (m, 10H), 5.55-5.16 (m 1H), 4.65 (m, 1H), 3.96 (m, 1H), 3.81 (m, 1/2H), 3.20 (m, 3H), 2.86 (m, 1H), 2.61 (m, 1H), 2.46 (m, 1/2H), 2.27 (m, 1/2H), 2.13 (m, 1H), 1.98 (s, 1/2H), 1.93 (s, 1H), 1.90 (s, 1H), 1.85 (s, 1/2H), (1.73-1.30 m, 7 1/2H), 0.85 (m, 1/2H), 0.12 (m, 1/2H) .FAB-MS:505.3 (M+1).
Example B23 (cis, d
1)
In the intermediate (87mg) of example B12 steps A preparation, add 1ml TFA.After 10 minutes, mixture concentrates, with methylbenzene azeotropic (3 *).Residue is dissolved in the ethyl acetate, washs with sodium bicarbonate solution.Organic layer concentrates.In the 3ml of residue dichloromethane solution, add N-BOC-(2R)-amino-5-phenyl valeric acid (70mg), EDC (55mg) and HOBT (35mg).After a few hours, in the reactant mixture impouring water, use dichloromethane extraction, with dried over sodium sulfate, filtration, concentrated.
In the intermediate of steps A preparation, add 1ml TFA.After 10 minutes, mixture concentrates, with methylbenzene azeotropic (3 *).In the 3ml of residue dichloromethane solution, add BOC-Alpha-Methyl alanine, EDC, HOBT and triethylamine.After a few hours, in the reactant mixture impouring water, use dichloromethane extraction, with dried over sodium sulfate, filtration, concentrated.Residue provides two kinds of diastereomers with MPLC (hexane/ethyl acetate=2/1) purification, and productive rate is 75% (the diastereomer d that polarity is more weak
1, 54mg; The diastereomer d that polarity is stronger
2, 53mg).
In the more weak diastereomer (54mg) of the polarity of step B preparation, add 1ml TFA.After 10 minutes, mixture concentrates, with methylbenzene azeotropic (3 *).Residue is dissolved in the ethyl acetate, washs with sodium bicarbonate.Organic layer dried over sodium sulfate, filtration, concentrated.Residue is dissolved in the ether, to wherein adding the HCl diethyl ether solution, provides a kind of white solid (d
1, 40mg).
1H NMR (400MHz, CD
3OD rotamer mixture): 7.23 (m, 10H), 5.08 (m, 1H), 4.76 (m, 1H), 4.21 (m, 1H), 3.80 (m, 2 1/2H), 3.47 (m, 1/2H), 3.26-2.99 (m, 4H), 2.86 (m, 1/2H), 2.63 (m, 2H), 2.40 (m, 1/2H), 1.75 (m, 4H), 1.63 (s, 2H), 1.60 (s, 2H), 1.57 (s, 2H), 0.95 (t, 7Hz, 2H), 0.87 (t, 7Hz, 1H) .FAB-MS:494.1 (M+1).
Desirable d
2Chemical compound (40mg) is with the stronger diastereomer (53mg) of the polarity that obtains among the example B23 step B, prepares according to the described step of example B23 step C.
1H NMR (400MHz, CD
3OD rotamer mixture): 7.23 (m, 10H), 4.91 (m, 1H), 4.75 (m, 1H), 4.03 (m, 1H), 3.81 (m, 2H), 3.45 (m, 1/2H), 3.26-2.96 (m, 4H), 2.71 (m, 2 1/2H), 2.40 (m, 1H), 1.90-1.64 (m, 4H), 1.63 (s, 2H), 1.61 (s, 3H), 1.59 (s, 3H), 0.93 (t, 7Hz, 3H) .FAB-MS:494.3 (M+1).
Under agitation, in the 4ml alcoholic solution of the intermediate that example B12 steps A-1 prepares, add 4N sodium hydroxide (4ml).Reactant mixture is in stirring at room 16 hours, vacuum evaporation.The residue dilute with water is used the 0.5N hcl acidifying, uses extracted with diethyl ether then.Organic layer dried over sodium sulfate, filtration, concentrated.Add ethylamine hydrochloride (74mg), EDC (115mg), HOBT (49mg) and triethylamine (83ml) in the 3ml dichloromethane solution of residue (100mg).After a few hours, in the reactant mixture impouring water, use dichloromethane extraction.With dried over sodium sulfate, filtration, concentrated.Residue provides expecting compound (74mg) with MPLC (hexane/ethyl acetate=1/1) purification.
Step B:
The intermediate (74mg) that obtains with steps A prepares according to step described in the example B12 steps A, provides expecting compound (60mg).
The intermediate (60mg) that obtains with step B prepares according to step described in example B23 steps A, B and the C, provides expecting compound (15mg).
1H NMR (400MHz, CD
3OD, the mixture of diastereomer and rotamer): 7.27 (m, 10H), 4.91 (m, 1H), 4.67 (m, 1H), 3.96 (m, 1H), 3.42 (m, 1/2H), 3.26-2.59 (m, 9 1/2H), and 1.90-1.64 (m, 4H), 1.64-1.57 (m, 6H), 0.79 (t, 7Hz, 3/2H), 0.77 (t, 7Hz, 3/2H) .FAB-MS:493.3 (M+1).
Add 0.080g 20% palladium dydroxide/C in the 20ml alcoholic solution of the 0.80g chemical compound that example B7 step B prepares, hydrogenation is 3 hours under atmospheric pressure.Catalyst leaches with one deck kieselguhr, and filtrate concentrates, and provides title compound.
Example B26, B27, B28, B29
Chemical compound shown in the following table B1 is to prepare from intermediate 4 in two steps.The acid intermediate in dichloromethane solution room temperature in the presence of EDC and DMAP with alcohol or amine coupling, these purification of intermediate, handle with hydrochloric acid (gas) ethyl acetate solution, the chemical compound among the table B1 is provided.
Steps A:
In the 5ml ethyl acetate solution of the piperidines intermediate of 1.1g example B7 steps A preparation, feed 10 seconds of HCl (gas) in room temperature, stirred 30 minutes.Remove solvent, the oily residue alkalizes with sodium bicarbonate aqueous solution, uses CH
2Cl
2Extraction.K is used in the organic layer salt water washing that merges
2CO
3Dry, filtration, concentrated provide 0.90g viscous crude shape amine.To the 20ml of above-mentioned intermediate CH
2Cl
2Add 0.97g (2R)-N-t-BOC-5-phenylpentanoic acid, 0.45g HOBT and 0.80g EDC in the solution, in stirred overnight at room temperature.In the reactant mixture impouring saturated sodium bicarbonate aqueous solution, use CH
2Cl
2Extraction.The Organic substance that merges is used MgSO with 0.50N hydrochloric acid solution, salt water washing
4Dry, filtration, concentrated.Residue is the anxious chromatography purification of sudden strain of a muscle of eluant in order to hexane-acetone (5: 1), provides a pair of product of about 2.0g.
Above-mentioned intermediate at room temperature, at 20ml CH
2Cl
2Middle with 2ml trifluoroacetic acid processing 1 hour.On rotary evaporator, remove volatile matter, residue NaHCO
3CH is used in the aqueous solution alkalization
2Cl
2Extraction.The organic layer K that merges
2CO
3Dry, filtration, concentrated.Residue is dissolved in CH
2Cl
2In, in the presence of 0.40g HOBT and 0.70g EDC with the coupling of 0.60g N-t-BOC-Alpha-Methyl alanine.Reactant mixture stirs and spends the night, and carries out post processing by the above.Residue is the eluant anxious chromatography purification of sudden strain of a muscle with hexane-acetone (5: 1), provides colourless foam shape title compound.
1H NMR (400MHz, CDCl
3The rotamer mixture): 7.40-6.85 (m, 14H), 5.10 (s, 2H), 5.05-4.88 (m, 2H), 4.70-4.60 (m, 1H), 3.93 (d, 1/2H), 3.85 (d, 1/2H), 3.10-2.85 (m, 4H), 2.70-2.50 (m, 5H), 1.85-1.60 (m, 7H), 1.50 (s, 3H), 1.48and1.47 (2s, 3H), 1.42 (s, 9H), 1.40-1.20 (m, 1H).
Approximately the intermediate that obtains of 0.050g steps A was dissolved in the 1ml ethyl acetate, adds the saturated HCl of 1ml (gas) ethyl acetate solution, stirring at room 30 minutes.Reactant mixture is cooled to 0 ℃, adds ether, and evaporating solvent stays cystose expection product.
1H NMR (400MHz, CD
3OD rotamer mixture): 7.40-7.00 (m, 14H), 5.10 (s, 2H), 4.90 (m, 1H), 4.58 (d, 1H), 3.95and3.90 (2doublets, 1H), 3.20-2.95 (m, 4H), 2.80-2.60 (m, 5H), 1.85-1.60 (m, 9H), 1.62 (s, 3H), 1.60 (s, 1H), 1.40 (m, 1H).
Example B31
Steps A:
Add 0.10g 20% palladium dydroxide in the 5ml methanol solution of the intermediate that 0.90g example B30 steps A prepares, under atmospheric pressure hydrogenation spends the night.Leach catalyst with one deck kieselguhr, use methanol wash.Filtrate concentrates, and the residue vacuum drying provides the acid of a kind of colourless foam shape, and need not purification can use.
Do interpolation 0.14ml triethylamine and 0.07ml ethyl chloroformate in the THF solution to the 10ml of the sour intermediate that the 0.30g steps A prepares, stirred 1 hour.Reaction stops with the 2ml ammonium hydroxide aqueous solution, uses CH
2Cl
2Extraction.The organic layer that merges is used MgSO with 0.50N salt acid elution
4Dry, concentrated.Residue is the eluant anxious chromatography purification of sudden strain of a muscle with chloroform-methanol (95: 5), and a kind of solid is provided, and uses the HCl deprotection as the above in ethyl acetate, provides the white solid title compound.
1H NMR (400MHz, CD
3OD rotamer mixture): 8.15 (t, 1H), 7.30-7.00 (m, 9H), 4.90 (m, 1H), 4.70 (d, 1H), 4.05and3.95 (2 are bimodal, 1H), 3.30-2.95 (m, 4H), 2.90-2.60 (m, 3H), 2.50 (bs, 2H), 1.90-1.65 (m, 7H), 1.60 (2 are unimodal, 6H), 1.48 (m, 1H).
Example 32-34 and 49
Chemical compound is a synthetic intermediate from example B31 steps A described in the table B2, utilizes example B5 title compound to prepare used chemical preparation.Other amine of the following stated is used for replacing ethanolamine, and final deprotection carries out in ethyl acetate and anhydrous hydrochloric acid.Generally make the hydrochlorate precipitation with ether.
M/e value of calculation (m+1)
5ml 1 to the sour intermediate of 0.50g example B31 steps A preparation adds 0.16g phosphinylidyne diimidazole in the 2-dichloroethane solution, stirred 30 minutes at 60 ℃.Reaction is cooled to room temperature, and half is handled with 0.12g 2-amino-pyrazol to get it then, 60 ℃ of heating 1 hour, is cooled to room temperature, stirs 2 days.In the reactant mixture impouring 0.50N aqueous hydrochloric acid solution, use CH
2Cl
2Extraction.MgSO is used in the organic layer salt water washing that merges
4Dry, concentrated, residue is that eluant dodges anxious chromatography purification with hexane-acetone (1: 1).Purifying mass provides the white solid title compound with above-described HCl/EtOAc scheme deprotection.FAB MS m/e value of calculation: C
32H
42N
6O
3558: actual measurement is straight: 559.2 (m+1)
This title compound is according to example B5 described such preparation, but with morpholino for ethanolamine.
1H NMR (400MHz, CDCl
3The rotamer mixture): 7.30-6.95 (m, 9H), 4.95 (m, 1H), 4.68 (d, 1H), 4.00and3.95 (2doublets, 1H), 3.59 (m, 4H), 3.35 (m, 4H), 3.25-2.90 (m, 4H), 2.80 50 (m, 5H), 1.90-1.65 (m, 7H), 1.63 (s, 3H), 1.60 (s, 3H), 1.47 (m, 1H).
At 0 ℃, under agitation, in the solution of the piperidines intermediate that 5.0g example B1 step B prepares, add 5ml triethylamine and 2.8ml CBZ-Cl.Allow reaction go back up to room temperature, stirring is spent the night.In the reactant mixture impouring aqueous ammonium chloride solution, use CH
2Cl
2Extraction.Organic layer is used MgSO with 0.50N HCl solution washing
4Dry, concentrated.This thick residue is dissolved in the 25ml methanol-water, adds 3 Equivalent Hydrogen sodium oxide, stirs 2 hours.Reactant mixture is acidified to pH=2 with 2N HCl, extracts with EtOAc.The organic layer that merges with the salt water washing, use Na
2SO
4Dry, concentrated, provide cystose acid.
Step B:
To the 10ml of the above-mentioned sour intermediate of 0.225g CH
2Cl
2Add 0.12g benzsulfamide, 0.093g DMAP and 0.164g EDC in the solution, stirring is spent the night.(Na is used in 2 * 10ml) washings to reactant mixture with 0.50NHCl
2SO
4Dry, concentrated.Thick residue is dissolved among 10ml methanol and the 0.10g 10%Pd/C, spends the night at the 40psi hydrogenation.Catalyst leaches with one deck kieselguhr, and filtrate concentrates, and provides to need not the piperidines that purification can use.
Now, allow this piperidines intermediate and intermediate 3 couplings, as the above, use the HCl/EtOAc deprotection, provide the white solid title compound.FAB MS m/e value of calculation (C
35H
44N
4O
5S) 632: measured value: 633.1 (m+1)
Steps A:
This intermediate prepares described in example B37 steps A like that, but with dimethyl dicarbonate butyl ester replaced C BZ-Cl.
Step B:
Under agitation, do interpolation 2.5ml triethylamine and 1.25ml ethyl chloroformate in the THF solution, stirred 30 minutes to the 30ml of the acid that the 2.90g steps A prepares.Remove the 10ml reactant mixture.Remaining mixture stirred 30 minutes with 20ml ammonium hydroxide aqueous solution cessation reaction, extracted with EtOAc.The organic layer that merges is used Na with 0.50N HCl, salt water washing
2SO
4Drying, filtration, evaporation provide a kind of oily residue.This material is dissolved in 20mlCH at 0 ℃
2Cl
2In the 20ml pyridine, add 1.1ml POCl
3, stirred 30 minutes.In the reactant mixture impouring saline, with 0.50N HCl solution, saturated NaHCO
3Na is used in solution, salt water washing
2SO
4Dry, concentrated.Residue is the anxious chromatography purification of sudden strain of a muscle of eluant with hexane-ethyl acetate (5: 1), provides the expection product.
Step C:
In the nitrile intermediate 20ml toluene solution of 0.10g step B preparation, add the folded ammonification tin trimethyl of 1.96g, reflux 18 hours.The excessive azide that is precipitated out during with cool to room temperature leaches.Filtrate concentrates, and tells half.Add 10ml EtOAc and trace carbinol in half to this, fed HCl (gas) 5 minutes, stirred 1 hour.Add ether, concentrate, provide a kind of gluey material, the washing of reuse ether, vacuum drying provide a kind of brown solid.400MHz NMR (CD
3OD) disclosing this is desirable tetrazolium intermediate.
Add 0.47g intermediate 3,0.16g HOBT, 0.45ml N-methylmorpholine and 0.29g EDC more than 0.30g in the 10ml chloroformic solution of synthetic piperidine hydrochlorate, stirring is spent the night.In the reactant mixture impouring 0.50N HCl solution, use CHCl
3Extraction, the organic layer of merging salt acid elution is used Na
2SO
4Dry, concentrated, provide a kind of gluey residue, again with CHCl
3-MeOH-NH
4OH (85: 15: 1) uses for eluant and dodges anxious chromatography purification.This provides 0.15g expection product.
This material is to prepare by the above EtOAc/HCl scheme from the intermediate that step C prepares.
1H HMR (400MHz, CD
3OD rotamer mixture): 8.15 (t, 1H), 7.60-7.05 (m, 9H), 4.90 (m, 1H), 4.60 (d, 1H), and 4.05and3.95 (2doublets, 1H), 3.30-3.10 (m, 4H), 3.10-2.60 (m, 5H), 1.90-1.65 (m, 9H), 1.60 (s, 6H), 1.50 (m, 1H).
Example B39
In the 2ml dry acetone solution of the intermediate that 0.030g example B38 step C prepares, add 13mg powder potassium carbonate and 0.006ml methyl iodide, in stirred overnight at room temperature.In the reactant mixture impouring saline, use CHCl
3Extraction.Na is used in the organic layer salt water washing that merges
2SO
4Drying, filtration, evaporation provide alkylate, are not further purified by EtOAc/HCl scheme deprotection again.This provides the title compound of 0.006g isomer mixture form.FAB MS m/e value of calculation (C
30H
41N
7O
2) 531: measured value 532.3 (m+1)
This intermediate is to prepare in the mode that is similar to preparation BOC material among the example B38 step B.
Step B:
Under 0 ℃ of stirring, in the dried alcoholic solution of 10ml of the nitrile that the 1.0g steps A prepares, fed HCl (gas) 1 hour.Reactant is added a cover, and is stored in the fridge to spend the night.Feed N
2Gas made excessive HCl (gas) remove in 1 hour, added ether, precipitated to induce imines-ether intermediate, but only formed a kind of oily material.Therefore, remove solvent on rotary evaporator, gluey residue is dissolved in CH
2Cl
2In, evaporate twice.Add ether now, this provides cystose imines-ether hydrochloride.
In the 5ml of the above-mentioned intermediate of 0.20g dichloroethane solution, add 0.073ml diisopropylethylamine and 0.030g formylhydrazine, in stirred overnight at room temperature.In the reactant mixture impouring water, use CH
2Cl
2Extraction.Na is used in the Organic substance salt water washing that merges
2SO
4Dry, concentrated.The residue that obtains thus is dissolved in the 5ml dimethylbenzene, the reflux some hrs.The reactant mixture cool to room temperature, evaporation dimethylbenzene.Residue hydrogenation 2 hours in 2ml methanol and 40mg 20% palladium dydroxide catalyst.Under the described in front standard EDC/HOBT condition of the piperidines that obtains thus with intermediate 3 couplings.Crude product is with CH
2Cl
2-MeOH-NH
4OH (95: 5: 1) is anxious chromatography purification for eluant dodges.Under the EtOAc/HCl condition, remove the BOC blocking group, provide the white solid title compound.
1H NMR (400MHz, CD
3OD rotamer mixture): 9.15 (s, 1H), 8.16 (bs, 1H), 7.30-7.00 (m, 9H), 4.90 (m, 1H), 4.60 (bs, 1H), 4.10 and 3.95 (2 are bimodal, 1H), 3.30-3.00 (m, 4H), 3.00-2.60 (m, 5H), 1.90-1.60 (m, 9H), 1.62 (s, 3H), 1.60 (s, 3H), 1.40 (m, 1H).
This title compound prepares in the mode that is similar to example B40, but replaces the N-formylhydrazine with N-methoxycarbonyl hydrazine.
1H NMR (400MHz, CD
3OD rotamer mixture): 7.30-7.02 (m, 9H), 4.90 (m, 1H), 4.60 (d, 1H), 4.05 and 3.95 (2 are bimodal, 1H), and 3.30-2.95 (m, 5H), 2.80-2.60 (m, 4H), 1.90-1.70 (m, 9H), 1.60 (s, 3H), 1.59 (s, 3H), 1.39 (m, 1H).
In the 50ml benzole soln of the sour intermediate of 3.0g example B37 steps A preparation, add 0.70ml oxalyl chloride and 3 DMF, stirring at room 2 hours.Steam benzene, residue is dissolved in the acetone at 0 ℃.Add the 5ml aqueous solution of 1.59g Hydrazoic acid,sodium salt, stirred 1 hour at 0 ℃.Reactant mixture separates organic layer with ether and water dilution.Na is used in organic layer salt water washing
2SO
4Dry, concentrated, provide the oily residue.This material dissolution in dried toluene, reflux 4 hours.Reactant mixture concentrates, and the isocyanates that obtains thus leaves in the electric refrigerator.
Add 0.80ml triethylamine and 0.20g methylamine hydrochloride in the toluene solution of this isocyanates of 0.40g, stirring is spent the night.Reactant mixture impouring NaHCO
3In the aqueous solution, extract with EtOAc.MgSO is used in the organic layer salt water washing that merges
4Dry, concentrated, provide and need not the methyl urea that purification can use.
Step B:
The piperidines intermediate of steps A preparation is used Pd (OH) in methanol
2Hydrogenation removes the CBZ blocking group, with intermediate 3 couplings, purification, with the above EtOAc/HCl scheme deprotection, provides title compound.
1H NMR (400MHz, CD
3OD rotamer mixture): 8.10 (m, 1H), 7.40-7.00 (m, 9H), 4.95 (m, 1H), 4.63 (d, 1H), (2 are bimodal, 1H) for 4.10and4.00,3.40-3.10 (m, 4H), 2.85-2.90 (m, 2H), 2.70 (s, 3H), 2.80-2.60 (m, 3H), 1.90-1.62 (m, 7H), 1.63 (s, 3H), 1.60 (s, 3H), 1.40 (m, 1H).
The isocyanates intermediate (0.20g) of example B42 steps A preparation refluxes in 5ml 6N HCl aqueous solution and spends the night.Reactant mixture washs with ether, and the ether layer removes.Water layer alkalizes to pH=10 with wet chemical, uses CH
2Cl
2Extraction.K is used in the organic layer salt water washing that merges
2CO
3Drying concentrates.This thick amine is handled with mesyl chloride and triethylamine in dichloromethane, makes it to change into Methanesulfomide.After the standard post processing, remove the CBZ group with hydrogenation method, elaborate title compound previously discussed.
1H NMR (400 MHz, CD
3OD rotamer mixture): 7.30-7.00 (m, 9H), 4.85 (m, 1H), 4.55 (d, 1H), 4.00 and 3.90 (2 are bimodal, 1H), 3.30-3.10 (m, 4H), 2.95-2.83 (m, 2H), 2.80 (2s, 3H), 2.80-2.60 (m, 3H), 1.90-1.65 (m, 9H), 1.60 (s, 3H), 1.56 (s, 3H), 1.55 (m, 1H).
Example B44
Steps A:
In the 100ml methanol solution of the pyridine aldehydes intermediate that 5.0g example B1 steps A prepares, add 4.0g Cyanogran., 5ml glacial acetic acid and 20g manganese dioxide, stirred 2 hours.These solids leach with one deck kieselguhr, and filtrate concentrates.Residue is collected with the 100ml saturated sodium bicarbonate solution, with 3 * 100ml ethyl acetate extraction.Na is used in the organic layer salt water washing that merges
2SO
4Dry, concentrated, the pyridine acid methyl ester is provided.This material dissolution adds the saturated HCl ethyl acetate solution of 5ml in methanol, concentrate, and provides hydrochlorate.
In the 15ml of the above-mentioned pyridine hydrochloride of 2g methanol solution, add the 0.225g platinum oxide, on the Parr shaking machine in 50psi hydrogenation 2 hours.Catalyst leaches with one deck kieselguhr, uses methanol wash.Filtrate concentrates, and provides 2.17g cystose pyridine hydrochloride.
This title compound is the chemical compound made from steps A and intermediate 3 by the above preparation.
1H NMR (400MHz, CD
3OD rotamer mixture): 8.10 (t, 1H), 7.78-(dd, 1H), 7.50-7.00 (m, 8H), 4.90 (m, 1H), 4.55 (d, 1H), 3.94 and 3.90 (2 are bimodal, 1H), 3.85 (s, 3H), 3.80-3.60 (m, 1H), 3.05 (dt, 1H), 2.70-2.50 (m, 4H), 1.90-1.50 (m, 6H), 1.55 (s, 3H), 1.50 9s, 3H), 1.40 (m, 1H).
To be the ester intermediate for preparing from example B44 steps A prepare in the mode that is similar to example B38 and prepares tetrazole compound this title compound.
1NMR (400MHz, CD
3OD rotamer mixture): 7.60-7.45 (m, 2H), 7.45-7.38 (m.2H), 7.30-7.10 (m, 5H), 4.90 (m, 1H), 3.95 and 3.90 (2 are bimodal, 1H), 3.30-3.00 (m, 2H), and 2.80-2.55 (m, 4H), 1.90-1.63 (m, 7H), 1.65-1.50 (4 singletstates, 6H), 1.40 (m, 1H).
Example B46
Steps A:
This chemical compound is to prepare in the mode that is similar to the synthetic protected nipecotic acid chemical compound of example B37 steps A.
Step B:
This intermediate is from the synthetic chemical compound of steps A, uses the phosphinylidyne diimidazole method described in the example B35 to prepare, but replaces amino-pyrazol with Aminotetrazole.
This chemical compound is piperidines intermediate and the intermediate of making from step B 3, utilizes the above chemical method of introducing synthetic.FAB MS m/e value of calculation (C
28H
36N
8O
3) 532: measured value 533.1 (m+1)
Steps A:
In the 10ml alcoholic solution of the imines one ether intermediate that 0.30g example B40 step B prepares, add the 0.124g dihydroxy acetone, heated 16 hours in 60 ℃ under the ammonia atmosphere in tube sealing.Reactant mixture is cooled to room temperature, evaporating solvent.Residue provides the expection product that 0.129g still has other impurity contamination with dodging anxious chromatography purification.
Step B:
The intermediate of steps A preparation remove the CBZ blocking group, with intermediate 3 couplings, purification with after using foregoing EtOAc/HCl scheme deprotection at last, elaborate title compound.
1H NMR (400MHz, CD
3OD rotamer mixture): 8.18 (2 three peaks, 1H), 7.30 (s, 1H), 7.30-7.00 (m, 9H), 4.90 (m, 1H), 4.56-4.55 (unimodal overlapping one bimodal, 3H), (2 are bimodal, 1H) for 4.05-3.95,3.30-2.95 (m, 4H), 2.95-2.60 (m, 5H), 1.90-1.65 (m, 7H), 1.63 (s, 3H), 1.60 (s, 3H), 1.45 (m, 1H).
Steps A:
Do interpolation 0.20g lithium aluminium hydride reduction in the THF solution at 0 ℃ of 50ml, in stirred overnight at room temperature to the ester of 1.0g example B1 step B preparation.Make reaction terminating at 0 ℃ with 10ml water and 10ml 30% sodium hydrate aqueous solution.Precipitate leaches, washs with EtOAc.Acetic acid ethyl ester extract with the salt water washing, use Na
2SO
4Dry, concentrated.This thick alcohol is dissolved in 30mlCH
2Cl
2In, add 1.3ml triethylamine and 1.4g dimethyl dicarbonate butyl ester at 0 ℃, then stirring at room 2 hours.The saturated NaHCO of reactant mixture impouring
3In the solution, use CH
2Cl
2Extraction.The organic layer that merges 0.50N HCl, salt water washing, concentrated.This material is that eluant dodges anxious chromatography purification with hexane-acetone (5: 1).
The alcohol that more than obtains is dissolved in 10ml CH at 0 ℃
2Cl
2In, add 0.45ml triethylamine and 0.14ml mesyl chloride, stirred 1 hour.The reactant mixture dilute with water, use CH
2Cl
2Extraction.The organic layer that merges is used Na with 0.50N HCl, salt water washing
2SO
4Dry, concentrated.This thick methylsulfonyl thing is done among the DMF and 0.20g 1,2 at 10ml, and the 4-triazole sodium salt is together 60 ℃ of heating 3 hours.The reactant mixture cool to room temperature, use the aqueous ammonium chloride solution cessation reaction.(3 * 15ml) extract reactant mixture with ether.The organic layer that merges with the salt water washing, use Na
2SO
4Dry, filtration, concentrated.This provides and need not the triazole product that purification can use.
Step B:
BOC in the steps A on synthetic piperidines protection removes with foregoing TFA step, by with intermediate 3 couplings, purification with the final deprotection of EtOAc/HCl scheme, elaborates title compound.FAB NS m/e value of calculation (C
31H
42N
6O
2) 530: measured value 531.4 (m+1)
Example B50
Prepare described in example B40 step B, but replace intermediate 3 with intermediate 1.
1H NMR (400MHz, CD
3OD rotamer mixture): 8.32 and 8.20 (2 bimodal, and 1H), 7.65 and 7.58 (2 bimodal, 1H), 7.40 and 7.35 (2 are bimodal, 1H), 7.25-7.00 (m, 6H), 6.50 (d, 1H), 5.30-5.20 (m, 1H), 4.58 and 4.55 (22 bimodal, 1H), 4.10 and 3.95 (2 are bimodal, 1/2H), 3.90 (d, 1/2H), and 3.40-3.00 (m, 7H), 2.70-2.45 (m, 3H), 2.80-2.50 (m, 2H), 1.60 (s, 6H), 1.34 (d, 1H), 0.95 (d, 1/2H), 0.70 (dt, 1/2H).
Do interpolation 0.196g phosphinylidyne diimidazole in the THF solution to the 3.3ml of the sour intermediate that 3.30g example B15 steps A prepares, 60 ℃ of heating 2 hours.Take out an aliquot reactant mixture, in surplus solution, add 0.10ml 4-amino butanol, heated 2 hours.Reactant mixture concentrates, with chloroform collect, wash with water twice, use 1M K
2HPO
4, saline each the washing once, use MgSO
4Dry, filtration, concentrated provide a kind of residue, and reuse prepares type TLC (1mm plate) with CHCl
3-MeOH-NH
4OH (90: 10: 1) provides the expection intermediate for eluant separates.
In the 2ml of the above-mentioned material of 0.20g methoxybenzene solution, add 3~4ml TFA, left standstill 30 minutes in room temperature.Decompression removes volatile matter, and residue is at chloroform and 1M K
2HPO
4Between distribute, alkalize to pH>9 with NaOH.Organic facies is separated the water chloroform extraction.MgSO is used in the organic layer salt water washing that merges
4Dry, filtration, concentrated.Provide one brood lac, reuse prepares type TLC (1mm plate) with CHCl
3-MeOH-NH
4OH (90: 10: 1) provides the expection product for eluant separates.
1H NMR (200MHz, CDCl
3The rotamer mixture): 8.24 (d, J=8); 7.42-7.07 (m); (6.16 " dd ", J=12,4); 4.97-4.8 (m); 4.69 (bd, J=13); (3.93 " bt ", J~10); 3.75-3.64 (m); 3.54-3.4 (m); 3.35-3.16 (m); 3.07 (quart., J=13); 2.77-2.5 (m); 1.97-1.42 (m); 1.34 (s) ..FAB MS value of calculation C
31H
44N
4O
4: MW=536.34; Measured value m/e=(m+1) 537.1.
0.150g the solution of above-mentioned free alkali with 0.50ml acetic acid and the dense HCl lyophilization of 0.030ml, provide title compound.
Prepare with the mode that is similar to the prepared chemical compound of Embodiment B 50A, but replace the 4-amino butanol with ethanolamine.
1H NMR (200MHz, CDCl
3The rotamer mixture): 8.22 (d, J=8); 7.45-7.05 (m); (6.58 dt, J=16,5); 4.88 (bs); 4.64 (bd, J=12); 3.90 (t, J=11); 3.79 (bs); 3.65-3.50 (m); 3.25-3.15 (m); 3.05 (quart., J=12); 2.8-2.5 (m); 2.32 (vbs); 2.0-1.77 (m); 1.77-1.45 (m); 1.35 (s) .FAB MS value of calculation C
29H
40N
4O
4: MW=508.30; Measured value m/e=(m+1) 509.2.
0.029g the solution of above-mentioned free alkali provides title compound with 0.50ml acetic acid and the dense HCl lyophilization of 0.010ml.
Example B50C
Steps A:
To the intermediate of 0.379g example B44 steps A preparation (by alkalizing to pH>9 with NaOH, using CHCl
3The 20ml of the free alkali extraction preparation) does and adds 5.5ml 1M lithium aluminium hydride reduction THF solution in the THF solution, and stirring is spent the night.Make reaction terminating with 10ml 30%NaOH aqueous solution, drain organic facies, the paste ethyl acetate extraction.The organic layer MgSO that merges
4Dry, concentrated.Residue provides the expection amino alcohol with preparation type TLC (1mm plate) purification.
1H NMR (200MHz, CDCl
3The rotamer mixture): 7.38-7.13 (m); 4.75 (s); 3.22 (bd, J=12Hz); 3.1-2.92 (m); 2.81 (td, J=10,4Hz); 2.13 (bs); 1.85-1.6 (m).
The intermediate of steps A preparation according to above-described standard EDC/HOBT scheme with (2R)-coupling of N-t-BOC-5-phenylpentanoic acid, with preparation type TLC (1mm plate) purification.
To the 2ml of the above-mentioned a pair of product of 0.145g CDCl
3Add 0.50ml 2-chloroethyl isocyanate in the solution, 60 ℃ of heating 6 hours, in the room temperature standing over night.This mixture is the preparation type TLC separation of eluant with hexane-EtOAc (1: 1), provides 0.11g expection carbamate.
1H NMR (200MHz, CDCl
3The rotamer mixture): 7.45-7.05 (m); 5.50 (bd, J=6); 5.19 (s); 5.14 (bs); 4.86-4.45 (bdd?); 4.11 (bd, J=7); 3.93 (bt, J=12); 3.72-3.42 (bm); 3.2-2.88 (m); 2.8-2.5 (bm); 1.95-1.55 (m); 1.44 (s).
The intermediate EtOAc/HCl deprotection of step B preparation, the hydrochlorate that obtains thus under standard EDC/HOBT condition with the coupling of N-t-BOC-Alpha-Methyl alanine.This material is eluant preparation type TLC (1mm plate) purification with hexane-EtOAc-(1: 1).
1H NMR (200MHz; CDCl
3The rotamer mixture): 7.40-7.04 (m); 5.19 (s); 5.17 (bs); 4.98 (s); 4.92 (bs); 4.72 (bd, J=13); 4.54 (bd, J=13); 4.18-4.04 (m); 3.95 (bt, J=13); 3.68-3.45 (m); 3.2-2.85 (m); 2.78-2.47 (m); 2.0-1.6 (m); 1.6-1.4 (m); 1.44 (s).
The about above-mentioned product of 85mg (0.13mmole) 1.0ml DMSO-d
6Collect, to wherein adding 38mg (0.37mmole) LiOAc2H
2O and 30mg (0.2mole) NaI; This solution is heated overnight in 80 ℃ of oil baths.Then, it is one brood lac reactant mixture to be become.Then it is distributed in CHCl
3In the mixture of water, anhydrous MgSO is separated, used to organic facies
4Drying, filtration, concentrating under reduced pressure become one brood lac after, one 8 " * 8 " * 1, on the 000m plate with 1: 1 EtOAc: hexane is that eluant is prepared type TLC purification, provides the 85mg title compound.
1H NMR (200MHz, CDCl
3The rotamer mixture): 7.40-7.04 (m); 5.19 (s); 5.17 (bs); 4.98 (s); 4.92 (bs); 4.72 (bd, J=13); 4.54 (bd, J=13); 4.18-4.04 (m); 3.95 (bt, J=13); 3.68-3.45 (m); 3.2-2.85 (m); 2.78-2.47 (m); 2.0-1.6 (m); 1.6-1.4 (m); 1.44 (s) .:7.4-7.0 (m); 7.88-7.69 (bm); 5.4 (s); 5.14 (s); 4.95-4.74 (m); 4.67 (bd, J=12); 4.38 (bd, J=13); 4.15-4.02 (m); 3.93 (bt, J=14); 3.50-3.30 (m); 3.18-2.8 (m); 2.75-2.35 (bm); 2.01 (s); 1.9-1.7 (bm); 1.5-1.3 (m); 1.40 (s).
In the 0.5ml methanol solution of the intermediate that 49mg step C obtains, add the dense H of 1~2ml
2SO
4After the standing over night, add 1M K
2HPO
4Solution is done the reactant mixture receipts under nitrogen current, and residue is distributed in CHCl
3With 1M K
2HPO
4Between, transfer to pH>9 with NaOH.Remove organic facies, water CHCl
3Extract several times again.The anhydrous MgSO of organic facies that merges
4Drying, filtration, concentrating under reduced pressure.Formed glue is one 8 " * 8 " * 1, on the 000m silica gel G F plate with 1: 10: 90 (dense NH
4OH: MeOH: CHCl
3) be prepared type TLC purification; Observe two master tapes.Dai separation faster provides title compound.
1H NMR (200MHz; CDCl
3The rotamer mixture): 7.4-7.05 (m); 5.44-5.12 (m); 5.18 (s); 5.12-4.8 (m); 5.05 (s); 4.69 (bd, J=12); 4.52 (bd, J=12); 4.12 (bs); 3.93 (bt, J=12); 3.78-3.63 (m); 3.44-3.24 (bm); 3.24-2.83 (m); 2.83-2.5 (m); 2.01-1.6 (m); 1.6-1.35 (m); 1.45 (s) .FABMS value of calculation C
35H
50N
4O
7: MW=638.37; Measured value m/e=(m+1) 639.3.
The 0.5ml acetic acid solution of the above-mentioned free alkali of 23mg (0.042mmole) is handled with the dense HCl of 0.005ml (0.06mmole) in a phial, and shell is freezing, lyophilizing is spent the night, and provides title compound.
In the 25ml alcoholic solution of the intermediate that 4.1g example B12 steps A-1 prepares, add 25ml 6N NaOH, stirred 12 hours.This mixture dilute with water is used extracted with diethyl ether.Organic layer is abandoned.Water layer is cooled to 0 ℃, with dense HCl acidify, uses extracted with diethyl ether then.Organic layer provides slightly acid of 2.57g with dried over sodium sulfate, filtration, concentrated.This thick acid (438mg) is dissolved in the methanol, uses Pd (OH) under 1 atmospheric pressure
2Hydrogenation 16 hours.Mixture is by diatomite filtration, and the filtrate vacuum concentration provides expecting compound (370mg).
In the chloroformic solution of the intermediate (100mg) that steps A prepares, add morpholine (0.35ml) EDC (95mg) and HOBT (49mg).Reactant mixture is stirring at room 12 hours, with dichloromethane dilution, water and salt water washing then.Organic layer dried over sodium sulfate, filtration, concentrated.Residue provides expection product (71mg) with preparation type TLC (hexane/ethyl acetate=1/1) purification.
Step C:
In the ethyl acetate solution of the intermediate (71mg) that step B prepares, fed HCl (gas) 15 seconds at 0 ℃.Allow mixture leave standstill 30 minutes, concentrated, provide a kind of solid (64mg) in room temperature.In the 2ml chloroformic solution of this thick material (32mg), add intermediate 1 (43mg), EDC (29mg), HOBT (15mg) and triethylamine (21ml).Reactant mixture in the impouring water, is used dichloromethane extraction stirring at room 3 hours, with dried over sodium sulfate, concentrate.Purification (preparation type TLC, methylene chloride=20/1) provides two kinds of diastereomer (d
1, the diastereomer that polarity is more weak, 14mg; d
2The diastereomer that polarity is stronger, 16mg).
Less diastereomer (the d of polarity of step C preparation
1, 14mg) be dissolved in the ethyl acetate, handled 15 seconds with HCl (gas) at 0 ℃.After 30 minutes, mixture concentrates in room temperature, provides expection product (10mg).FAB-MS:546.3(M+1)
Example B52 (cis, d
2)
This title compound (12mg) is the stronger diastereomer (d of polarity that obtains with example B51 step C
2, 16mg) prepare according to the described step of example B51 step D.FAB-MS:546.3(M+1)
The chemical compound 1~7th of table shown in the B3 prepares according to the step of above report (in the coupling step with different amine).Details sees example B51 step B, C and D for details.
Table B3
R FAB-MS (M+1) 1 d
1+ d
2Thiomorpholine 562.22 d
1-d
2Pyrrolidine 530.23 d
1+ d
2N methyl piperazine 559.34 d
1+ d
2Piperidines 544.35 d
1+ d
2Ethanolamine 520.26 d
1+ d
2Dimethylamine 504.37 d
1+ d
2Glycine ethyl ester 562.3
The ethyl acetate solution of the intermediate of example B51 step B preparation was handled 15 seconds with HCl (gas) at 0 ℃, left standstill 30 minutes in room temperature.Mixture is concentrated into dried, provides thick material.Add N-t-BOC-O-benzyl-D-serine (107mg), EDC (92mg), HOBT (47mg) and triethylamine (67mg) in the 3ml chloroformic solution of this thick material (99mg), stirring at room 3 hours, in the impouring water.The mixture dichloromethane extraction is used dried over sodium sulfate, concentrates.Residue provides expection product (97mg) with RPLC (chromatatron, methylene chloride=20/1) purification.
Step B:
The ethyl acetate solution of the intermediate (97mg) of steps A preparation was handled 15 seconds with HCl (gas) at 0 ℃, left standstill 30 minutes in room temperature.Reactant mixture concentrates and provides a kind of residue, and it is dissolved in the 2ml chloroform, reacts with N-t-BOC-Alpha-Methyl alanine (52mg) in the presence of EDC (62mg), HOBT (36mg) and triethylamine (40ml).After 64 hours, in the reactant mixture impouring water, use dichloromethane extraction in room temperature.The extract that merges provides a kind of residue with dried over sodium sulfate, filtration, concentrated, and reuse RPLC (chromatatron, methylene chloride=20/1) purification provides two kinds of diastereomer (d
1, the diastereomer that polarity is more weak, 65mg; d
2, the diastereomer that polarity is stronger, 23mg).
Step C:
More weak diastereomer (the d of polarity of step B preparation
1, 65mg) in ethyl acetate, handled 15 seconds with HCl (gas) at 0 ℃.After room temperature left standstill 30 minutes, mixture concentrated, and provided expection product (58mg).FAB-MS:537.4(M+1)
Example B54 (cis, d
2)
This title compound (20mg) is the stronger diastereomer (d of polarity that obtains with example B53 step C
2, 23mg) prepare according to step described in the example B51 step D.FAB-MS:537.3(M+1)
Chemical compound 1~6th shown in the table B-4 prepares by the above (with different amine).These synthetic details can be consulted example B51 step B and example B53 steps A, B and C.
R FAB-MS (M+1) 1 d
1+ d
2Thiomorpholine 553.32 d
1+ d
2Pyrrolidine 521.33 d
1N methyl piperazine 550.44 d
2N methyl piperazine 550.45 d
1+ d
2Piperidines 535.46 d
1+ d
2Dimethylamine 495.2
The intermediate of example B51 step B preparation was handled 15 seconds with HCl (gas) at 0 ℃ in ethyl acetate.Reactant mixture left standstill 30 minutes in room temperature, concentrated, and provided crude product.In the 10ml chloroformic solution of this material (209mg), add intermediate 3 (295mg), EDC (202mg), HOBT (105mg) and triethylamine (147ml), stirring at room 16 hours, in the impouring water.The mixture dichloromethane extraction, with dried over sodium sulfate, concentrated, residue provides expection product (387mg) with RPLC (chromatatron, methylene chloride=20/1) purification.This non-enantiomer mixture was handled 15 seconds with HCl (gas) at 0 ℃ in ethyl acetate, left standstill 30 minutes in room temperature.Reactant mixture concentrates, and provides expection product (330mg).FAB-MS:535.3
Chemical compound is the set step (replacing morpholine with ethanolamine) that illustrates with example according among example B51 step B and example B53 steps A, B and the C shown in the table B5, prepares with intermediate 3.
Table B5
R FAB-MS (M+1) 1 d
1Ethanolamine 509.12 d
2Ethanolamine 509.2
Example B56 (cis, d
1+ d
2)
Steps A:
In benzene (80ml) solution of the intermediate (1.15g) of example B51 steps A preparation, add oxalyl chloride (365ml) and DMF (2) at 0 ℃, stirred 10 minutes and stirring at room 2 hours at 0 ℃, concentrated, provide acyl chlorides.In 0 ℃ of acetone (10ml) solution, add water (3ml) solution of Hydrazoic acid,sodium salt (741mg), stirring at room 45 minutes to this acyl chlorides.The mixture extracted with diethyl ether, MgSO is used in water, salt water washing
4Drying, filtration, evaporation provide acid azide, and it is dissolved in the toluene (35ml), reflux 12 hours, provide isocyanates (1.02g).
The intermediate (55mg) of steps A preparation and toluene (5ml) solution of 2-(methyl mercapto) ethamine (147mg) refluxed 1 hour.Make reaction terminating with 1N HCl, use extracted with diethyl ether, use dried over sodium sulfate then.Concentrate, purification (chromatatron, methylene chloride=20/1), provide the urea of expection.The BOC blocking group is deprotection under the above condition, provides expection product (40mg).
In the 2ml chloroformic solution of the intermediate (20mg) that step B prepares, add intermediate 1 (28mg), EDC (19mg), HOBT (10mg) and triethylamine (14ml).Reactant mixture is stirring at room 16 hours, in the impouring water.The mixture dichloromethane extraction is used dried over sodium sulfate.Concentrated, purification (chromatatron, methylene chloride=20/1) provide the expection product.This mixture is handled with HCl in EtOAc, provides end product (6mg).FAB-MS:565.3(M+1)
Chemical compound is to prepare according to determined step (with different amine or alcohol) shown in the table B6.
R FAB-MS (M+1) 1 d
1+ d
2Ethanol 520.32 d
1+ d
2Morpholine 561.43 d
1+ d
2Ethanolamine 535.34 d
1+ d
2Ethamine 519.2
Example B57 (cis, d
1+ d
2)
In the 1ml chloroformic solution of the intermediate (20mg) that example B56 step B prepares, add intermediate 3 (28mg), EDC (19mg), HOBT (10mg) and triethylamine (14ml).Reactant mixture is stirring at room 16 hours, in the impouring water.The mixture dichloromethane extraction is used dried over sodium sulfate.Concentrate and purification (chromatatron, methylene chloride=20/1), provide the expection product.This non-enantiomer mixture HCl/EtOAc deprotection provides end product (8mg).FAB-MS:554.4(M+1)
Chemical compound shown in the table B7 is to prepare according to the above step (with ethanol and different amine).
Table B7
R FAB-MS (M+1) 1 d
1+ d
2Ethanol 509.32 d
1+ d
2Morpholine 550.43 d
1+ d
2Ethanolamine 524.34 d
1+ d
2Thiomorpholine 566.2
Steps A:
In the alcoholic solution of the intermediate (2.52g) that example B14 steps A obtains, add 6N NaOH.Mixture refluxed 3 hours, concentrated then.The residue dilute with water is used the 0.5N hcl acidifying, uses extracted with diethyl ether.Organic layer provides expection product (2.12g) with dried over sodium sulfate, filtration, concentrated.
In the 1ml chloroformic solution of the intermediate (15mg) that steps A prepares, add 4-amino-1-butanols (9ml), EDC (19mg) and HOBT (7.5mg).Reactant mixture is stirring at room 2 hours, in the impouring water.This mixture dichloromethane extraction is used dried over sodium sulfate.Concentrate and purification (chromatatron, methylene chloride=20/1), provide the expection product.
The intermediate of step B preparation HCl/EtOAc scheme deprotection.In the 1ml of this thick material chloroformic solution, add intermediate 1 (18mg), EDC (19mg), HOBT (7.5mg) and triethylamine (20ml).Reactant mixture is stirring at room 4 hours, in the impouring water.This mixture dichloromethane extraction is used dried over sodium sulfate.Concentrated and purification (PLC, methylene chloride=10/1) provides expection product (200mg, inseparable non-enantiomer mixture), handles with HCl (gas) in EtOAc again, provides expection product (18mg).
1H NMR (400MHz, CD
3The mixture of OD diastereomer and rotamer): 7.73 (d, 8Hz, 1/2H), 7.65 (d, 8Hz, 1/2H), (7.54-6.98 m, 7 1/2H), 6.87 (t, 7Hz, 1 1/2Hz), 5.25 (m, 1H), 4.53 (m, 1H), 3.89 (m, 1H), and 3.39-2.47 (m, 10H), 1.71-0.93 (m, 5H), 1.61 (s, 3/2H), 1.60 (s, 3H), 1.58 (s, 3/2H), 0.41 (m, 1/2H), 0.11 (m, 1/2H) .FAB-MS:548.2 (M+1).
Chemical compound is to prepare according to above step (with different amine) shown in the table B8.
Table B8
R FAB-MS (M+1) 1 d1+d2 ethamine 504.32 d1+d2 morpholines 546.33 d1+d2 ethanolamine 520.24 d1
556.15 d2
556.1
Steps A:
In the chloroformic solution of the intermediate (915mg) of example B58 steps A preparation, add (1R, 2R)-N-methyl isoephedrine (590ml), EDC (1.14g) and catalytic amount DMAP.Reactant mixture is stirring at room 12 hours, in the impouring water.This mixture dichloromethane extraction is used dried over sodium sulfate.Concentrated and purification (MPLC, hexane/ethyl acetate=3/1) provides two kinds of diastereomer (d
1, the diastereomer that polarity is more weak, 316mg; d
2, the diastereomer that polarity is stronger, 138mg).
The methanol solution of the intermediate (138mg) that the polarity of steps A preparation is stronger is used Pd (OH) under an atmospheric pressure
2/ C hydrogenation a few hours.The mixture diatomite filtration, filtrate concentrates.Residue is dissolved in the ether, with 1N salt acid elution.Water layer is abandoned.Organic layer provides expection product (84mg) with dried over sodium sulfate, filtration, concentrated.
In the chloroformic solution of the intermediate (16mg) that step B prepares, add glycine ethyl ester hydrochloride (21mg), EDC (19mg), HOBT (13mg) and triethylamine (35ml).After 3 hours, mixture dilutes with dichloromethane in room temperature, then water and salt water washing.Organic layer dried over sodium sulfate, filtration, concentrated.Residue provides expection product (16mg) with preparation type TLC (hexane/ethyl acetate=1/1) purification.
The intermediate (8mg) of step C preparation is handled with HCl (gas) in EtOAc, provides a kind of crude salt hydrochlorate.In the 1ml of this thick material chloroformic solution, add intermediate 1 (8mg), EDC (8mg), HOBT (5mg) and triethylamine (8ml).Reactant mixture is stirring at room 12 hours, in the impouring water.The mixture dichloromethane extraction is used dried over sodium sulfate.Concentrated and purification (PLC, hexane/ethyl acetate=1/2) provides the expection product, and reuse HCl/EtOAc scheme deprotection provides expection product (11mg).
1H NMR (400MHz, CD
3OD rotamer mixture): 7.73 (d, 8Hz, 1/2H), 7.54 (d, 8Hz, 1/2H), 7.38-6.99 (m, 8H), 6.84 (d, 7Hz, 1H), 5.28-5.05 (m, 2H), and 4.80-4.52 (m, 1H), 4.09 (m, 3H), 3.59 (m, 1 1/2H), 3.34 (m, 1 1/2H), 3.24 (m, 1H), 2.98 (m, 1H), 2.70-2.48 (m, 2 1/2H), 1.70-1.55 (m, 1 1/2H), 1.61 (s, 3H), 1.60 (s, 3H), 1.22 (t, 7Hz, 3H), 1.00 (m, 1/2H), 0.57 (m, 1/2H). FAB-MS:562.3 (M+1)
Chemical compound prepares according to step shown in the above example B59 shown in the table B9.
R FAB-MS (M+1) 1 d
2Beta-alanine ethyl ester 576.32 d
2L-methyl lactamine 562.3
Example B60 (trans, d
2)
The intermediate (8mg) of example B59 step C preparation was handled 15 seconds with HCl (gas) at 0 ℃ in ethyl acetate, left standstill 30 minutes in room temperature, was concentrated into driedly, provided thick material.In the 1ml of this thick material chloroformic solution, add intermediate 3 (8mg), EDC (8mg), HOBT (5mg) and triethylamine (8ml).Reactant mixture is stirring at room 12 hours, in the impouring water.This mixture dichloromethane extraction is used dried over sodium sulfate.Concentrated and purification (PLC, hexane/ethyl acetate=1/2) provides the expection product, handles with HCl (gas) in EtOAc again, and title compound (11mg) is provided.FAB-MS:551.4(M+1)
Chemical compound prepares according to above step (with the different aminoacids coupling) shown in the table B10.
Table B10
R FAB-MS (M+1) 1 d
2Beta-alanine ethyl ester 565.42 d
2L-methyl lactamine 551.4
In the methanol solution of the intermediate (200mg) that example B12 steps A prepares, add the catalytic amount methanol solution of sodium methylate, reflux a few hours.In the mixture impouring 0.1N hydrochloric acid, use extracted with diethyl ether.Organic layer with dried over sodium sulfate, filtration, concentrate, provide the expection product (190mg).
-78 ℃ in the 2ml toluene solution of the intermediate (120mg) of steps A preparation, add diisobutylaluminium hydride (the 1N hexane solution, 0.49ml).Reactant mixture after 1 hour, makes reaction terminating with methanol, then in the impouring 0.5N hydrochloric acid solution-78 ℃ of stirrings.This mixture extracted with diethyl ether.Organic layer dried over sodium sulfate, filtration, concentrated.Residue provides expection product (60mg) with PLC (hexane/ethyl acetate=3/1) purification.
In the THF of phosphine triethyl acetate solution (5ml), 0 ℃ add two (trimethyl silyl) ammonification potassium (the 0.5N toluene solution, 1.45ml).After 1 hour, THF (1ml) solution of the intermediate (42mg) of step B preparation adds in this phosphorane solution, refluxes 1 hour in room temperature.This mixture concentrates, and residue provides the expection product with PLC (hexane/ethyl acetate=4/1) purification.
In the intermediate (50mg) of step C preparation, add 0.5ml TFA in room temperature.After 10 minutes, mixture concentrates, with methylbenzene azeotropic (3 *).In the 1ml of this residue chloroformic solution, add intermediate 1 (62mg), EDC (53mg), HOBT (23mg) and triethylamine (58ml).Mixture is stirring at room 3 hours, in the impouring water.Mixture with dichloromethane extraction, use dried over sodium sulfate.The purification of this residue (PLC, hexane/ethyl acetate=1/1) provides a pair of product (65mg).
The methanol solution of the intermediate (50mg) of step D preparation is used Pd (OH) under an atmospheric pressure
2/ C hydrogenation a few hours.The mixture diatomite filtration, filtrate concentrates.Residue is handled with HCl (gas) in EtOAc, provides expection product (36mg).FAB-MS:533.3(M+1)
Ethyl chloroformate (12.9ml) adds in Cu-lyt. (1.35g) THF (200ml) suspension that stirring is arranged.At 0 ℃, slowly add ethyl nicotinate solution, add subsequently Grignard reagent (according to
J.Org.Chem.,
5, step described in 3490 (1986), from 2-bromobenzaldehyde (25g), 1, ammediol (20ml) and magnesium (4.9g) preparation).Reactant mixture stirred 1 hour, in impouring saturated ammonium chloride/ammonia solution (1/1), used ethyl acetate extraction.Organic layer is used dried over sodium sulfate with 1N hydrochloric acid and salt water washing.Evaporating solvent provides the expection product.The ethyl acetate crystallization of this material provides 25g expection product.
Step B:
The intermediate (25g) of steps A preparation is dissolved in the hot ethyl acetate (500ml), then cool to room temperature.This organic solution is used PtO under an atmospheric pressure
2Hydrogenation a few hours (monitoring) with TLC.The mixture diatomite filtration, the filtrate vacuum concentration.Residue is dissolved in the hot ethanol (150ml), uses 6N NaOH (75ml) reflow treatment 10 minutes.The mixture vacuum concentration added water in residue, stirring at room 10 minutes.Collect the pale solid with Filtration.Filtrate is used dichloromethane extraction, uses the salt water washing, uses dried over sodium sulfate.Solvent concentrates, and merges with the pale solid, provides 13.6g expection product.
Step C:
In THF (300ml) solution of the intermediate (10.1g) of step B preparation, add catalytic amount indicator (bromocresol green) and NaCNBH at 0 ℃
3(64mmole).In this reactant mixture, add 1N hydrochloric acid and kept (pH=4.0) until yellow.After 1 hour, among this mixture impouring 1N NaOH, use chloroform extraction.Organic layer salt water washing is with dried over sodium sulfate, concentrated.Residue removes the very strong material of depolarization with methylene chloride=10/1 and carries out purification by filtered through silica gel.The substance dissolves that obtains after filtrate concentrated is added triethylamine (6ml) and CBZ-Cl (4.6ml) at 0 ℃ in this mixture in chloroform.Stir after 15 minutes, in the reactant mixture impouring water, use dichloromethane extraction.Dried over sodium sulfate is used in organic layer salt water washing.Concentrated and purification (MPLC, hexane/ethyl acetate=5/1) provides expection product (6.4g).
In methanol (30ml) solution of the intermediate (2.17g) that step C prepares, add 1N hydrochloric acid (5ml), stirred 1 hour.In the mixture impouring 1N NaOH solution, use extracted with diethyl ether.Dried over mgso is used in organic layer salt water washing.Residue purification (chromatatron, hexane/ethyl acetate=5/1) provides expection product (1.56g).
Step e:
0 ℃ in the THF of phosphine triethyl acetate solution (25ml), add two (trimethyl silyl) ammonification potassium (the 0.5N toluene solution, 4.56ml)., THF (10ml) solution of the intermediate (860mg) of step D preparation is added in this phosphorane solution after 1 hour in stirring at room in room temperature.This mixture makes reaction terminating with 1N hydrochloric acid then stirring at room 1 hour.This mixture with extracted with diethyl ether, with the salt water washing, use dried over mgso.Residue purification (chromatatron, hexane/ethyl acetate=5/1) provides expection product (873mg).
The intermediate (870mg) of step e preparation is dissolved in the methanol, uses Pd (OH) under an atmospheric pressure
2/ C hydrogenation 1.5 hours.Mixture is by diatomite filtration, filtrate vacuum concentration.In the chloroformic solution of residue, add intermediate 3 (749mg), EDC (714mg) and HOBT (276mg), stirred 2 hours.Mixture concentrates and purification (chromatatron, hexane/ethyl acetate=2/1) provides two kinds of diastereomers (545mg, the diastereomer that polarity is more weak, d
1500mg, the diastereomer that polarity is stronger, d
2)
Step G:
Ethyl acetate solution to the more weak diastereomer (200mg) of the polarity of step F preparation fed HCl (gas) 15 seconds at 0 ℃.After room temperature left standstill 30 minutes, mixture concentrated and purification (LH-20,100% methanol), provides white solid cis d
1Product (100mg).
1H NMR (400MHz, CD
3OD rotamer mixture): 7.28-7.06 (m, 9H), 5.09 (m, 1/2H), 4.85-4.55 (m, 1 1/2H), 4.17 (m, 1H), 4.10 (q, 7Hz, 2H), 3.77 (m, 2H), 3.46 (m, 1 1/2H), 3.25 (m, 1/2H), 3.15-2.39 (m, 9H), 1.89-1.60 (m, 5H), 1.65 (s, 2H), 1.62 (s, 2H), 1.57 (s, 2H), 1.21 (t, 7Hz, 3H), 0.91 (t, 7Hz, 3/2H), 0.85 (t, 7Hz, 3/2H) .FAB-MS:594.3 (M+1)
Desirable cis d
2Product (3.3mg) is the stronger diastereomer of polarity that obtains with example B62 step F, prepares according to the described step of example B62 step G.
1H NMR (400MHz, CD
3OD rotamer mixture): 7.90-7.03 (m, 9H), 4.92-4.61 (m, 2H), 4.10 (q, 7Hz, 2H), 4.07 (m, 1H), 3.79 (m, 2H), 3.45 (m, 1 1/2H), 3.25 (m, 1/2H), 3.07-2.38 (m, 9H), 1.94-1.69 (m, 4H), 1.63 (s, 3/2H), 1.61 (s, 3/2H), 1.60 (s, 3/2H), 1.59 (s, 3/2H), 1.20 (t, 7Hz, 3H), 0.91 (t, 7Hz, 3H) .FAB-MS:594.3 (M+1).
Steps A:
In ethanol (1ml) solution of the more weak diastereomer (30mg) of the polarity of example B62 step F preparation, add 6N NaOH (30ml) in room temperature.Stir after 1 hour mixture is concentrated.In residue, add 1N hydrochloric acid, use ethyl acetate extraction.Organic layer salt water washing with dried over sodium sulfate, concentrated, provides expection product (20mg)
Step B:
In the 0.5ml chloroformic solution of the intermediate (6mg) that steps A prepares, add ethanolamine (0.8ml), EDC (3.5mg) and HOBT (1.8mg).Reactant mixture is in stirring at room a few hours, in the impouring water.The mixture dichloromethane extraction is used dried over sodium sulfate.Concentrate and purification (PLC, methylene chloride=20/1), propose a pair of product, this material is used the HCl deprotection in EtOAc, provide the cis d of expection
1Product (1.6mg).
1H NMR (400MHz, CD
3OD rotamer mixture): 7.28-7.07 (m, 9H), 5.09 (m, 1/2H), 4.85-4.62 (m, 1 1/2H), 4.19 (m, 1H), 3.75 (m, 2H), 3.55 (t, 6Hz, 2H), 3.45 (m, 1H), 3.34-2.84 (m, 6 1/2H), 2.73-2.45 (m, 51/2H), 1.85-1.57 (m, 5H), 1.65 (s, 3/2H), 1.62 (s, 3/2H), 1.57 (s, 3/2H), 1.56 (s, 3/2H), 0.92 (t, 7Hz, 3/2H), 0.85 (t, 7Hz, 3/2H) .FAB-MS:609.2 (M+1)
Example B65 (cis, d
1)
In the 0.5ml chloroformic solution of the intermediate (6mg) that example B64 steps A prepares, add ethylamine hydrochloride (1mg), EDC (3.5mg), triethylamine (4ml) and HOBT (1.8mg).Reactant mixture in the impouring water, is used dichloromethane extraction in stirring at room a few hours, uses dried over sodium sulfate.Residue purification (PLC, methylene chloride=20/1) provides a pair of product.This material is handled with HCl in EtOAc, obtains desirable cis d
1Product (1.5mg).
1H NMR (400MHz, CD
3OD rotamer mixture): 7.28-7.07 (m, 9H), 5.09 (m, 1/2H), 4.83-4.62 (m, 1 1/2H), 4.17 (m, 1H), 3.75 (m, 2H), 3.50 (m, 1 1/2H), (3.25-2.84 m, 6 1/2H), and 2.72-2.39 (m, 5H), 1.89-1.58 (m, 5H), 1.65 (s, 3/2H), 1.61 (s, 3/2H), 1.57 (s, 3/2H), 1.56 (s, 3/2H), 1.06 (t, 7Hz, 3H), 0.91 (t, 7Hz, 3/2H), 0.85 (t, 7Hz, 3/2H) .FAB-MS:593.3 (M+1)
Example B66 (cis, d
1)
In dichloromethane (1ml) solution of the intermediate (8mg) of example B64 steps A preparation, add ethyl chloroformate (2.3ml) and triethylamine (5ml) at 0 ℃.Reactant mixture stirred 10 minutes at 0 ℃, stirring at room 1 hour.In this mixture impouring saturated sodium bicarbonate solution, use dichloromethane extraction.The water washing of organic layer usefulness salt, usefulness dried over sodium sulfate, concentrated.In 0 ℃ of acetone (0.5ml) solution, add Hydrazoic acid,sodium salt (2.3mg) water (0.2ml) solution to residue.In stirring at room after one hour, the mixture extracted with diethyl ether, MgSO is used in water and salt water washing
4Dry.Filtration and evaporation provide acid azide, it is dissolved in the toluene (1ml) refluxed 3 hours, provide isocyanates.This toluene solution cool to room temperature, and the interpolation methylamine (40% aqueous solution, 9ml).After 12 hours, make reaction terminating in stirring at room, use dichloromethane extraction, then with dried over sodium sulfate, concentrated with 1NHCl.Residue purification (PLC, methylene chloride=20/1) provides the urea of expection, uses the HCl deprotection in EtOAc, produces expection product (3.5mg).FAB-MS:594.3(M+1)
The intermediate (17mg) of example B62 step e preparation is dissolved in the methanol, uses Pd (OH) under an atmospheric pressure
2/ C hydrogenation 1.5 hours.The mixture diatomite filtration, the filtrate vacuum concentration provides unhindered amina (11mg).In the chloroformic solution of this unhindered amina (5.5mg), add intermediate 1 (7mg), EDC (6mg) and HOBT (4mg).After 12 hours, mixture concentrates and purification (chromatatron, hexane/ethyl acetate=2/1) provides a kind of inseparable non-enantiomer mixture.This non-enantiomer mixture was handled 15 seconds with HCl (gas) at 0 ℃ in ethyl acetate, after room temperature leaves standstill 30 minutes.Mixture concentrates, and provides a kind of white solid (8mg).FAB-MS:605.3(M+1)
Steps A:
In 0 ℃ of THF (25ml) solution, add to diethyl phosphate cyano group methyl ester two (trimethyl silyl) ammonification potassium (the 0.5N toluene solution, 3.44ml)., after one hour THF (10ml) solution of the intermediate (650mg) of example B62 step D preparation is added in the phosphorane solution that is in room temperature in stirring at room.Mixture is used 1N hydrochloric acid cessation reaction then stirring at room one hour.This mixture extracted with diethyl ether is used the salt water washing, with dried over mgso, concentrated.Purification (chromatatron, hexane/ethyl acetate=5/1) provides α, and alpha, beta-unsaturated nitriles (trans, 466mg; Cis, 124mg).
The intermediate (590mg) of steps A preparation is dissolved in the methanol, uses Pd (OH) under an atmospheric pressure
2/ C hydrogenation 1.5 hours.The mixture diatomite filtration, the filtrate vacuum concentration.In the chloroformic solution of this residue, add intermediate 3 (560mg), EDC (560mg) and HOBT (208mg).After a few hours, mixture concentrates and purification (chromatatron, hexane/ethyl acetate=1/1) provides two kinds of diastereomers (220mg, the diastereomer that polarity is more weak, d
1260mg, the diastereomer that polarity is stronger, d
2).
Step C:
In toluene (5ml) solution of the more weak diastereomer (220mg) of the polarity of step B preparation, add Azide tin trimethyl (206mg), reflux
Hour.The vacuum removal solvent.Residue is dissolved in methylene chloride/acetic acid=20/1/0.1 (20ml), leaves standstill 12 hours in room temperature.The vacuum removal solvent.Residue provides expection product (120mg) with PLC (methylene chloride/acetic acid=20/1/0.1) purification.
The intermediate of step C (120mg) is handled with HCl in EtOAc, provides white solid expection cis d
1Product (98mg).
1H NMR (400MHz, CD
3OD rotamer mixture): 7.28-7.08 (m, 9H), 5.08 (m, 1/2H), 4.84-4.53 (m, 1 1/2H), 4.18 (m, 1H), 3.78 (m, 3H), 3.27-3.03 (m, 6H), 2.85-2.30 (m, 4H), 1.90-1.38 (m, 5H), 1.65 (s, 3/2H), 1.61 (s, 3/2H), 1.57 (s, 3/2H), 1.56 (s, 3/2H), 0.90 (t, 7Hz, 3/2H), 0.85 (t, 7Hz, 3/2H) .FAB-MS:590.2 (M+1).
Example B69 (cis, d
2)
This expection product (2mg) is the stronger diastereomer (6.8mg) of polarity that obtains with example B68 step B, prepares according to step described in example B68 step C and the D.FAB-MS:590.4(M+1)
Example B70 (cis, d
1)
The intermediate (782mg) of example B68 steps A preparation is dissolved in the methanol, uses Pd (OH) under an atmospheric pressure
2/ C hydrogenation 1.5 hours.The mixture diatomite filtration, the filtrate vacuum concentration.In the chloroformic solution of this residue, add BOC-D-tryptophan (468mg), EDC (534mg) and HOBT (207mg).After a few hours, mixture concentrates and purification (MPLC, hexane/ethyl acetate=1/1), provides two kinds of diastereomers (316mg, the diastereomer that polarity is more weak, d
1: the diastereomer that 300mg polarity is stronger, d
2).
Step B:
The more weak diastereomer (316mg) of the polarity of steps A preparation was handled 15 seconds with HCl (gas) at 0 ℃ in ethyl acetate.Left standstill 30 minutes in room temperature, mixture is concentrated into the dried thick material that provides.In the 5ml of this residue chloroformic solution, add N-BOC-Alpha-Methyl alanine (158mg), EDC (149mg), triethylamine (217ml) and HOBT (77mg), stirring at room 12 hours.In the mixture impouring water, use dichloromethane extraction.Use the salt water washing.Organic layer dried over sodium sulfate, filtration, concentrated.Residue provides expecting compound (287mg) with chromatatron (hexane/ethyl acetate=1/2) purification.
Step C:
Desirable cis d
1Product (135mg) is to prepare according to example B68 step C and the described step of D from the intermediate (287mg) that above example B70 step B prepares.
1H NMR (400MHz, CD
3OD rotamer mixture): 8.09 (d, 8Hz, 1/2H), 7.80 (d, 8Hz, 1/2H), 7.64 (d, 8Hz, 1/2H), 7.57 (d, 8Hz, 1/2H), 7.35 (d, 7Hz, 1H), 7.22-7.00 (m, 7H), 5.31-5.20 (m, 1H), 4.71 (d, 12Hz, 1/2H), 4.41 (d, 12Hz, 1/2H), 4.15 (m, 1/2H), 3.92-3.67 (m, 2 1/2H), 3.43-3.03 (m, 8 1/2H), 2.80 (m, 1H), 2.52-2.25 (m, 1 1/2H), 1.59 (s, 3/2H), 1.54 (s, 3/2H), 1.50 (s, 3/2H), 1.35 (3/2H), 1.43 (m, 1H), 0.93 (t, 7Hz, 3/2H), 0.84 (t, 7Hz, 3/2H) .FAB-MS:601.1 (M+1).
This title product (125mg) is according to example B70 step B and example B68 step C and the described step preparation of D from the stronger diastereomer (300mg) of the polarity of example B70 steps A preparation.
1H NMR (400MHz, CD
3OD rotamer mixture): 8.24 (d, 8Hz, 1/2H), 8.09 (d, 8Hz, 1/2H), 7.59 (d, 8Hz, 1/2H), 7.54 (d, 8Hz, 1/2H), 7.34-6.92 (m, 8H), 5.40 (m, 1/2H), 5.15 (m, 1/2H), 4.64 (d, 13Hz, 1/2H), 4.55 (d, 13Hz, 1/2H), 4.22 (m, 1/2H) .4.09 (m, 1/2H), and 3.81-3.58 (m, 21/2H), 3.40-2.84 (m, 9 1/2H), 2.71-2.2 (m, 1 1/2H), 1.63 (s, 3/2H), 1.52 (s, 3/2H), 1.48 (s, 3/2H), 1.29 (3/2H), 1.53 (m, 1/2H), 1.32 (m, 1/2H), 0.90 (t, 7Hz, 3/2H), 0.79 (t, 7Hz, 3/2H) .FAB-MS:601.2 (M+1).
Example B72 (cis, d
1+ d
2)
Steps A:
In methanol (3ml) solution of the intermediate (235mg) that example B62 step C prepares, add 1N hydrochloric acid (0.5ml), stirred 1 hour.In formed mixture, add NaCNBH
3(1.0N THF solution 0.7ml), with in the reactant mixture impouring 1N hydrochloric acid, is used extracted with diethyl ether after 5 minutes.Organic layer salt water washing is with dried over sodium sulfate, concentrated.Residue purification (chromatatron, hexane/ethyl acetate=1/1) provides expection product (142mg).
In the methanol solution of the intermediate (142mg) that steps A prepares, add HCl diethyl ether solution and Pd (OH)
2, under nitrogen atmosphere, stirred 12 hours.The mixture diatomite filtration, filtrate concentrates, and provides expection product (105mg).
Step C:
Add intermediate l (81mg), EDC (54mg), HOBT (28mg) and triethylamine (53ml) in the 2ml chloroformic solution of the intermediate (105mg) of step B preparation, reactant mixture is stirring at room 12 hours, in the impouring water.The mixture dichloromethane extraction is with dried over sodium sulfate, concentrated.The residue purification (chromatatron, handle with HCl in EtOAc again, provides expection product (56mg) by hexane/ethyl acetate=l/1) provide the expection product.FAB-MS:519.2(M+1)
Steps A:
0 ℃ in the acetone soln of the intermediate (100mg) of example B72 steps A preparation, add Jones reagent (4N, 0.2ml).After 16 hours, mixture isopropyl alcohol cessation reaction is used diatomite filtration in stirring at room.Filtrate is used ethyl acetate extraction.Organic layer salt water washing with dried over sodium sulfate, concentrated, provides expection product (100mg).
Step B:
0 ℃ in the diethyl ether solution of the intermediate (50mg) of steps A preparation, add Azimethylene. (Blatt,
Org.Syn.CollectiveVol.4, p225).Mixture slowly gos up to room temperature, stirs 12 hours.Residue concentrates and purification (PLC, hexane/ethyl acetate=3/1) provides expection product (50mg).
Step C:
The intermediate (50mg) of step B preparation is dissolved in the methanol, uses Pd (OH) under an atmospheric pressure
2/ C hydrogenation 1.5 hours.The mixture diatomite filtration, the filtrate vacuum concentration.In the chloroformic solution of residue, add intermediate 1 (48mg), EDC (45mg) and HOBT (24mg).After a few hours, mixture concentrates and purification (chromatatron, hexane/ethyl acetate=1/1), provides a pair of product.This material provides expection product (47mg) with HCl/EtOAc scheme deprotection.FAB-MS:563.1(M+1)
At example B73, add glycine ethyl ester HCl salt (51mg), EDC (46mg), triethylamine (84ml) in the chloroformic solution of the intermediate that steps A makes (5Omg), and HOBT (32mg).Reaction was under agitation carried out 12 hours in room temperature, poured in the water then.The mixture dichloromethane extraction with dried over sodium sulfate, concentrated and purification (PLC method, hexane/ethyl acetate=1/1), obtains this a pair of product (45mg).
According to example B73, the described program of step C, the intermediate (45mg) that is obtained by steps A makes title product (43mg).FAB-MS:634.2(M+1)。
Example B75 (cis, d
1+ d
2)
At example B73, add ethanolamine (12ml), EDC (37mg) and HOBT (19mg) in the chloroformic solution of the intermediate that steps A makes (53mg), at room temperature stirred 12 hours, pour in the water then.This mixture dichloromethane extraction is used dried over mgso, and concentrates.Residue purification (chromatatron, methylene chloride=20/1) is obtained this to product (29mg).
According to example B62, the described program of step F and G makes required product (16.8mg) by top intermediate (29mg).FAB-MS:58.2(M+1)。
At example B12, add PtO in the acetic acid solution of the intermediate that steps A-1 makes (100mg)
2, hydrogenation 24 hours (monitoring) under 1 atmospheric pressure then with TLC.Mixture concentrates filtrate by diatomite filtration, and residue is with the toluene azeotropic distillation.Residue is dissolved among the TFA, at room temperature stirred 20 minutes.Reactant mixture is concentrated, and residue is dissolved in the dichloromethane (0.5ml), and itself and intermediate 1 (15mg), EDC (15mg), HOBT (6mg) and triethylamine (11ml) are reacted.This mixture was at room temperature stirred 3 hours, be poured in the water then.The mixture dichloromethane extraction is used dried over sodium sulfate, concentrates.Residue obtains this to product through purify (PLC, hexane/ethyl acetate=1/1), it is handled obtaining required product (8mg) in EtOAc with HCl.FAB-MS:511.1(M+1)。
With example B12, the intermediate that step B makes is dissolved in the methanol, uses Pd (OH) under 1 atmospheric pressure
2Carried out hydrogenation 2 hours.This mixture is passed through diatomite filtration, filtrate vacuum concentration.In the residue that is dissolved in chloroform (1ml) (88mg), add N-BOC-β, beta-dimethyl--Beta-alanine (48mg, W.R.Schoen etc., J, Med.Chem., 37,897 (1 994)), EDC (48mg) and HOBT (30mg), stirred 12 hours, and then this mixture was poured in the water.The mixture dichloromethane extraction is used dried over sodium sulfate, and concentrates.Residue obtains this to product through purify (chromatatron, hexane/ethyl acetate=1/1), in EtOAc with HCl with its deblocking, obtain required product (58mg).FAB-MS:519.2(M+1)。
Example B78 (cis, d
1+ d
2)
Steps A:
At room temperature in dihydropyran (5ml) solution of (R)-methyl lactate (1ml), add 1 concentrated hydrochloric acid.Under agitation reacted 1 hour, and obtained required product (1.49g) through concentrating with chromatatron purification (hexane/ethyl acetate=3/1).(1N in cyclohexane extraction, 3.45ml), after 1.5 hours, ends this reaction with low-temp methanol to add diisobutylaluminium hydride at-78 ℃ in toluene (10ml) solution of the lactate (500mg) of this THP protection.Mixture is poured in 5% aqueous citric acid solution, uses extracted with diethyl ether then.Dried over sodium sulfate is used in organic layer salt water washing, obtains shielded aldehyde after concentrating.
In methanol (0.5ml) solution of the product (25mg) that example B77 makes, add intermediate (36mg) and the sodium acetate (18mg) that makes in the steps A, at room temperature stirred 1 hour.In this mixture, slowly add NaCNBH
3(1N in THF, 90ml), stirred 16 hours then, and concentrated.Residue obtains required product by chromatatron purification (methylene chloride/ammonium hydroxide=10/1/0.1), it is dissolved in the methanol (0.5ml), and handles with 9N hydrochloric acid (0.2ml).Stir after 2 hours mixture is concentrated, obtain required product (10.5mg) after the drying.FAB-MS:577.4(M+1)。
Steps A:
(21.8g, 100mmol) drips of solution in dichloromethane (200ml) is added to the nipecotic acid ethyl ester (15g is 95.4mmol) and in the solution that is stirring of DMAP (0.05 equivalent) in dichloromethane with Bis(tert-butoxycarbonyl)oxide with charging hopper at 0 ℃.This mixture was stirred 2-3 hour.This solution use anhydrous magnesium sulfate drying with 3N HCl and saturated sodium-chloride washing, filters then, the concentrated required product (18.7g, 88%) that obtains.
At-78 ℃, (28ml, (7g was 26.90mmol) in the solution that is stirring in THF (100ml) 28mmol) to join the N-t-Boc-3-piperidine ethyl formate with LHMDS with 10 fens clock times under argon shield.At-78 ℃ with solution restir 30 minutes; (4.8g 28mmol) slowly joins in this solution with benzyl bromide a-bromotoluene then.The reactant mixture stirring is spent the night, allow it be warmed to room temperature.This material is concentrated, and dilute with water is used ethyl acetate extraction (2 * 200ml) then.Organic layer anhydrous magnesium sulfate drying, filtration and concentrated.Dodge chromatograph with silicagel column and purify,, obtain title compound (8.32g, 88%) with the hexane solution eluting of 20% ethyl acetate.FAB-MS:C
20H
29NO
4: value of calculation: 347; Measured value: 348 (M+H).
(8g, ethyl acetate 23.02mmol) (80ml) solution is cooled to 0 ℃ to the intermediate that step B is made.While stirring hydrogen chloride body bubbling is entered into mixture, till saturated.Under agitation reacted 40 minutes, up to TLC the analysis showed that react completely till.Then with solution concentration to remove ethyl acetate, obtain this product (6.53g, 99%).
1H NMR (CDCl
3, 400MHz) δ 7.25-7.19 (m, 3H), 7.04-7.01 (m, 2H), 5.35 (v.br.s, 2H), 4.22-4.10 (m, 2H), 3.44 (d, J=13Hz, 1H), 3.21 (br.d, J=12.7Hz, 1H), 2.95 (d, J=13.5Hz, 1H), 2.76-2.68 (m, 3H), 2.22 (br.d, J=13Hz, 1H), 1.73-1.71 (m, 1H), 1.61-1.48 (m, 2H), 1.18 (t, J=7Hz, 3H) .FAB-MS:C
15H
21NO
2: value of calculation: 247; Measured value: 248 (M+H).
With EDC (1.5 equivalent) join the intermediate that preceding step makes (1.2g, 4.23mmol), intermediate 1 (1 equivalent), HOBT (1 equivalent), and in the solution of N-methylmorpholine (1 equivalent) in being cooled to 0 ℃ dichloromethane.Reactant mixture is spent the night 0 ℃ of stirring.This solution washs with saturated sodium-chloride, uses anhydrous magnesium sulfate drying; Filter then and concentrate.Purify by the MPLC method, with 40% ethyl acetate and hexane solution eluting, obtain two kinds of enantiopure compound, the chemical compound that comes out from chromatographic column earlier is designated as d
1(1.14g), this enantiomer has R-absolute stereo chemical constitution on the 3-position of 3-picoline formic acid esters; The chemical compound that comes out from chromatographic column in the back is designated as d
2(1.08g), this enantiomer has S-absolute stereo chemical constitution (referring to the example C2 that illustrates that conformation is arranged) on the 3-position of 3-picoline formic acid esters.d
1FAB-MS value of calculation C
35H
46N
4O
6: 618; Measured value: 619 (M+H) d
2FAB-MS value of calculation C
35H
46N
4O
6: 618; Measured value: 619 (M+H)
According to the described program of step C, the intermediate (1g) and the HCl gas that are made by preceding step prepared in 0 ℃ of reaction in ethyl acetate (25ml) in 1.5 hours.Product: 860mg, 91%.FAB-MS:C
30H
38N
4O
4: value of calculation: 518; Measured value: 519 (M+H).
Example C1A
According to the described program of example C1 step C, the 1g intermediate d that makes from example C1 step D
2Preparation, concrete grammar be in ethyl acetate (20ml) 0 ℃ by blasting HCl gas 30 minutes, obtain title compound (878mg, 93%) after the evaporation till saturated.FAB-MS:C
30H
38N
4O
4: value of calculation: 518; Measured value: 519 (M+H).
1H NMR (CD
3OD 400MHz) shows that this chemical compound exists with two kinds of rotamers, and its ratio is about 5/3, and these two kinds of isomers slowly change mutually with respect to the NMR time ruler.
δ7.60(d,J=7.9Hz,578H),7.55(d,J=7.9Hz,3/8H),7.34-6.93(m,9H),5.36(dd,J=5.2Hz,9.7Hz,3/8H),5.31(dd,J=6.7Hz,8.8Hz,5/8H),4.23(br.d,J=13.7Hz,3/8H),4.10-4.00(m,6/8H),4.04-3.98(m,3/8H),3.96-3.82(m,10/8H),3.80(br.d,J=13.5Hz,5/8H),3.36(br.d,J=13.3Hz,5/8H),3.29-3.22,3.17-3.10,(2m,2H),3.20(br.d,J=14.5Hz,3/8H),3.10-2.96(m,5/8H),2.90(s,6/8H),2.60(d,J=13.4Hz,5/8),2.41(d,J=13.4Hz,5/8H),2.19-2.12,1.82-1.70、1.68-1.60,1.50-1.40,1.34-1.25,1.05-0.95(6m,4H),1.55(s,9/8H),1.50(s.15/8H),1.09(t,J=7.1Hz,3H).
According to what establish above, the program that exemplifies to C as example C1 steps A has prepared other listed intermediate among the table C I.According to example C1 step D and E, and example C1a, prepared final chemical compound with intermediate 1.
Table CI: additional example
Midbody product
Midbody product sequence number Y MF MF isomer
a
FAB-MS(M+1)???????FAB-MS(M+1)1?????Me????????????????C
9H
17NO
2??????C
24H
34N
4O
4???d1
171(M
+,EI-MS)??443???????????????d22?????Et????????????????C
10H
19NO
2?????C
25H
36N
4O
4???d1
185(M
+,EI-MS)??457???????????????d23?????n-Pr??????????????C
11H
21NO
2?????C
26H
38N
4O
4???d1
199 (M
+, EI-MS) 471 d24 pi-allyl C
11H
19NO
2C
26H
36N
4O
4D1
198??????????????????469????????????????????d25?????n-Bu??????????????C
12H
23NO
2?????????C
27H
40N
4O
4????????d1
213(M
+,EI-MS)??????485????????????????????d26?????-CH2OEt???????????C
11H
21NO
3?????????C
26H
38N
4O
5????????RS
216 4877 cyclohexyl methyl C
15H
27NO
2C
30H
44N
4O
4D1
254??????????????????525????????????????????d28?????Ph(CH
2)
2-???????C
16H
23NO
2????????C
31H
40N
4O
4????????d1
261(M
+,EI-MS)??????533????????????????????d29?????Ph(CH
2)
3-???????C
17H
25NO
2????????C
32H
42N
4O
4????????d1
275(M
+,EI-MS)??????547????????????????????d210????o-MeOBn-??????????C
16H
23NO
3?????????C
31H
40N
4O
5????????d1
278??????????????????549????????????????????d211????m-MeOBn-??????????C
16H
23NO
3?????????C
31H
40N
4O
5????????d1
278??????????????????549????????????????????d212????p-MeOBn-??????????C
16H
23NO
3?????????C
31H
40N
4O
5????????d1
278??????????????????549????????????????????d213????o-Me-Bn-??????????C
16H
23NO
2?????????C
31H
40N
4O
4????????d1
262??????????????????533????????????????????d214????m-Me-Bn-??????????C
16H
23NO
2?????????C
31H
40N
4O
4????????d1
262??????????????????533????????????????????d215????p-Me-Bn-??????????C
16H
23NO
2?????????C
31H
40N
4O
4????????d1
262??????????????????533????????????????????d216????o-Cl-Bn-??????????C
15H
20NO
2Cl???????C
30H
37N
4O
4Cl??????d1
282,284(3∶1)???????554,556(3∶1)?????????d217????m-Cl-Bn-??????????C
15H
20NO
2Cl???????C
30H
37N
4O
4Cl??????d1
282,284(3∶1)???????554,556(3∶1)?????????d215????p-Cl-Bn-??????????C
15H
20NO
2Cl???????C
30H
37N
4O
4Cl??????d1
282,284(3∶1)???????554,556(3∶1)?????????d216????2,6-di-Cl-Bn-????C
15H
19NO
2Cl
2?????C
30H
36N
4O
4Cl
2
316,318,320????????587,589,59117????p-Br-Bn-??????????C
15H
20NO
2Br???????C
30H
37N
4O
4Br??????d1
326,328(1∶1)???????597,599(1∶1)?????????d218?????????m-Br-Bn-???????????????C
15H
20NO
2Br????????C
30H
37N
4O
4Br??????????d1
326,328 (1: 1) 597,599 (1: 1) d219 o-nitro-Bn-C
15H
20N
2O
4C
30H
37N
5O
6D1
293 564 d220 m-nitro-Bn-C
15H
20N
2O
4C
30H
37N
5O
6D1
293 564 d221 p-nitro-Bn-C
15H
20N
2O
4C
30H
37N
5O
6D1
293 564 d222 1-menaphthyl C
19H
23NO
2C
34H
40N
4O
4D1
298????????????????????569???????????????????????d2
24?????????BnO
2C-????????????????C
16H
21NO
4??????????C
31H
38N
4O
6????????????RS
292????????????????????56325?????????EtO
2C-????????????????C
11H
19NO
4??????????C
26H
36N
4O
6????????????RS
230????????????????????50126?????????p-Ph-Bn-???????????????C
21H
25NO
4???????????C
36H
42N
4O
4????????????d1
A: in each table of Ben Biao and back, be used for isomer labelling: R or S and be meant that stereochemical structure on X and the carbon atom that Y is connected, RS are meant in this two kinds of mixture of isomers in the heart; d
1Or d
2Represent that these two kinds of diastereomers are opened, and press example C1 step D definition.
According to example C1 step D and E, other listed examples among the table CIa that used intermediate 1 and commercially available intermediate preparation.
Midbody product
Product
Sequence number X MF isomer
FAB-MS(M+1)
1???????-OH????????C
20H
28N
4O
3?????????????RS
373
2??????-CH2OH??????C
21H
30N
4O
3?????????????RS
387
3??????-CO2Et??????C
23H
32N
4O
4?????????????RS
429
4??????CO2Bn???????C
28H
34N
4O
4?????????????RS
491
5??????CONMe2??????C
23H
33N
5O
3?????????????RS
428
According to example C1 step D and E, used intermediate 3 and shown some listed among C1 intermediate preparation other listed products among the table CIb.
Product sequence number Y MF isomer
FAB-MS(M+1)1??????????Bn????????????????????C30H41N3O4????????????????R
5082??????????Bn????????????????????C30H41N3O4????????????????S
5083??????????Ph(CH
2)
2???????????C31H43N3O4????????????????d1
522???????????????????????d24??????????Ph(CH
2)
3???????????C
32H
45N
3O
4????????????d1
536 d25 1-menaphthyl C
34H
43N
3O
4RS
558
7??????????p-Ph-Bn-??????????????C
36H
45N
3O
4????????????RS
5848??????????BnO
2C-???????????????C
31H
41N
3O
6????????????RS
According to example C1 step D and E, used intermediate 2 and shown some listed among CI intermediate preparation other listed products among the table CIc.
FAB-MS(M+1)1??????Bn??????????C29H39N3O5?????R
5102??????Bn??????????C29H39N3O5?????S
5103??????Et??????????C24H37N3O5?????RS
4484??????Ph(CH
2)
2?C30H41N3O5?????d1
524????????????d25??????Ph(CH
2)
3?C31H43N3O5?????d1
538????????????d26??????H???????????C22H33N3O5?????RS
420
With example C1, the intermediate that step C makes (50.8g) is dissolved in the dichloromethane, with 3N NaOH washing.The water layer dichloromethane extraction is with the solution drying (MgSO that merges
4) and evaporation, obtain being buttery unhindered amina.3-benzyl-nipecotic acid ethyl ester and D-tartaric acid (31g) are dissolved in 880ml water/acetone (1: 4) solution, simultaneously heating.Allow this solution stay refrigerator overnight, leach formed crystallization.At room temperature recrystallization in 470ml water/acetone (1: 4) obtains 3-(R)-benzyl-nipecotic acid ethyl ester D-tartrate (21g).
The structure of this chemical compound is by the assay determination of X-radiocrystallgraphy.Wherein the tartaric configuration of D-is known is S, S, and the configuration at chirality position is R after measured in this 3-benzyl-nipecotic acid ethyl ester salt.
With the mother liquid evaporation that merges, and, this mixture was stirred 30 minutes, organic layer is separated to wherein adding 3N NaOH and dichloromethane.Water layer dichloromethane extraction 2 times, the organic extract MgSO of merging
4Drying obtains 24.4g and is rich in the S-isomeric compound after the evaporation.At room temperature in 400ml water/acetone (1: 4) with L-tartaric acid (14.8g)-play crystallization, obtain 3 (S)-benzyl-nipecotic acid ethyl ester L-tartrate (27.3g).
1H NMR (CD
3OD, 400MHz) δ 7.31-7.22 (m, 3H), 7.12-7.09 (m, 2H), (4.40 s, 2H come from tartaric acid), and 4.30-4.10 (m, 2H), 3.49 (br.d, J=13Hz, 1H), 3.06 (d, J=13.6Hz, 1H), 2.98 (d, J=13Hz, 1H), 2.92 (dt, J=3.3Hz, 13Hz, 1H), 2.82 (d, J=13.6Hz, 1H), 2.30 (d, J=12.4Hz, 1H), 1.88 (td, J=3Hz, 14.5Hz, 1H), 1.69 (dt, J=3Hz, 13Hz, 1H), 1.63-1.51 (m, 1H), 1.25b (q, J=7.1Hz, 3H).
3 (S)-benzyl-nipecotic acid ethyl ester L-tartrate (39.74g) is suspended in 70ml 3N NaOH and the 70ml water, then uses dichloromethane extraction.With extract merging, dry and evaporation, obtain a kind of viscous crude.EDC (23g) break into portions is joined in this oil, N-t-Boc D-TrpOH (30.43g) and the solution that is stirring of HOBT (13.5g) in 0 ℃ of dichloromethane (200ml).This mixture stirring is spent the night.Be poured into then among water and the 3N HCl, use dichloromethane extraction.Organic layer is used MgSO with saline, saturated sodium bicarbonate washing
4Drying obtains crude product (67.7g) after the evaporation, need not further purification can directly use.FAB-MS:C
31H
39N
3O
5: value of calculation: 533: measured value: 534 (M+H).
Step C:
HCl gas bubbling is entered in the solution of intermediate (67.7g, crude product) in 0 ℃ of ethyl acetate (100ml) that preceding step makes, till saturated.Reactant mixture was stirred 30 minutes at 0 ℃, and excessive HCl and ethyl acetate are removed in evaporation then.Residue is suspended in the dichloromethane, with the mixture washing of 3N HaOH (70ml) and water (100ml).Organic layer MgSO
4Drying is evaporated to a little volume, need not to be further purified just to can be used for next step.FAB-MS:C
26H
31N
3O
3: value of calculation: 433; Measured value: 434 (M+H).
Intermediate, N-Boc-α-Me-AlaOH (20.3g) and the solution of DMAP (200mg) in dichloromethane that previous step is obtained suddenly at room temperature stir, and EDC (24g) is divided into several portions joins wherein.Reactant mixture was stirred 3 hours,,, carry out post processing with 3N HCl, saline and saturated sodium bicarbonate solution washing with the dichloromethane dilution.Organic layer MgSO
4Drying obtains a kind of viscous crude after the evaporation.Should pass through unmodified packed column by oil,, remove some strong polar impurities, obtain required compound (54.2g) with 60% ethyl acetate isohexane eluant solution.FAB-MS:C
35H
46N
4O
6: value of calculation: 618; Measured value: 619 (M+H).
HCl gas bubbling is entered into intermediate (54.2g) that preceding step the makes solution in 0 ℃ of ethyl acetate (100ml), till saturated.At 0 ℃ this reactant mixture was stirred 15 minutes, excessive HCl and ethyl acetate are removed in evaporation.Residue is dissolved in the dichloromethane (100ml), adds ethyl acetate (300ml) then.The mixture stirring is spent the night, and the solid collected by filtration thing obtains title compound (34g).Mother solution further is evaporated to a little volume, obtains second batch of product (10.1g).
MS is identical with example C1A with NMR result.
According to example C2, step B to F uses the aminoacid of the Boc protection that obtains easily to replace N-t-Boc-D-TrpOH to make other listed products among the table CII.
Product sequence number R MF
FAB-MS(M+1)1????4-F?????????C30H37N4O4F
5372????5-F?????????C30H37N4O4F
5373????6-F?????????C30H37N4O4F
5374????1-Me????????C31H40N4O4
5335????5-MeO???????C31H40N4O5
5496????5-HO????????C30H38N4O5
5357????6-MeO???????C31H40N4O5
549
Steps A:
(18.3g 83.7mmol) joins 3-pyrrolidine carboxylic acid carbethoxy hydrochloride (J.Chem.Soc., 24,1618-1619 at leisure with the di-tert-butyl dicarboxylate; 10g, 69.8mmol), in triethylamine (7.75ml) and the solution that is stirring of DMAP (857mg) in dichloromethane (40ml), formed mixture was at room temperature stirred 3 days.Then this mixture is concentrated, uses 3N HCl washing, dry and evaporation, obtain this intermediate.
According to example C1, the described program of step B, the intermediate that obtains by preceding step (500mg, 2.05mmol), KHMDS (512mg, benzyl bromide a-bromotoluene 2.57mmol) (371mg, 2.16mmol) preparation.Dodge chromatographic column with silica gel and purify,, obtain title compound (385mg, 56%) with 5-20% ethyl acetate and hexane solution eluting.
According to example C1, the described program of step C, the intermediate that obtains by preceding step (385mg, 1.16mmol) and HCl (gas in ethyl acetate (5ml) in 0 ℃ of reaction preparation (306mg, 98%) in 15 minutes.
According to example C1, the described program of step C, by the intermediate of preceding step preparation (138mg, 0.514mmol), intermediate 1 (200mg, 0.514mmol), HOBT (1 equivalent) N-methylmorpholine (1 equivalent), and EDC (2 equivalent) preparation.Purify with the MPLC method,, obtain this product (250mg, 80%) with the hexane solution eluting of 60% ethyl acetate.FAB-MS:C
34H
44N
4O
6: value of calculation: 604; Measured value: 605 (M+H).
According to example C1, the described program of step C, (250mg 0.036mmol) prepared in 0 ℃ of reaction in ethyl acetate (3ml) with HCl gas the intermediate that is made by preceding step in 10 minutes.FAB-MS:C
29H
36N
4O
4: value of calculation: 504; Measured value: 505 (M+H).
Example C4
At-78 ℃, under argon shield, ((4g is 15.7mmol) in the solution that is stirring in THF (100ml) 32mmol) to join the N-t-Boc-3-piperidine ethyl formate for 1M, 32ml with LHMDS in during 10 minutes.At-78 ℃ with this solution restir 30 minutes; Slowly add then methyl disulfide (1.92g, 20.37mmol).The reactant mixture stirring is spent the night, make it be warmed to room temperature.This material is concentrated, and dilute with water is with ethyl acetate extraction (2 * 200ml).Organic layer anhydrous magnesium sulfate drying, filtration and concentrated.Purify by the silica gel flash column chromatography, the hexane solution eluting with 20% ethyl acetate obtains this chemical compound.FAB-MS:C
14H
25NO
4S: value of calculation: 271; Measured value: 272 (M+H).
According to example C1, the described program of step C, (1g 3.3mmol) 35 minute makes this product (783mg, 99%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (25ml).FAB-MS:C
9H
17NO
2S: value of calculation: 171; Measured value: 271 (M+H).
According to example C1, the described program of step D, the intermediate that makes by preceding step (123mg, 0.514mmol), intermediate 1 (1 equivalent), HOBT (1 equivalent), NMM (1 equivalent) and EDC (197mg, 1.028mmol) preparation.The diastereomer of purifying and to obtain with the MPLC method.The chemical compound that comes out from chromatographic column earlier is designated as d
1(109mg, 37%); The chemical compound that comes out from chromatographic column in the back is designated as d
2(88mg, 30%).d
1FAB-MS value of calculation C
29H
42N
4O
6S:574; Measured value: 575 (M+H) d
2FAB-MS value of calculation C
29H
42N
4O
6S:574; Measured value: 575 (M+H)
According to example C1, the described program of step C, the intermediate d that makes by preceding step respectively
1(80mg) and d
2(80mg) and HCl gas in ethyl acetate (each 5ml) in 0 ℃ the reaction 20 minutes the preparation.d
1: (71mg, 99%) d
2: (70mg, 98%) d
1 1H NMR (CD
3OD, 400MHz): this chemical compound ratio is about two kinds of rotamers existence of 1: 1.δ 7.71 (d, J=7.2Hz, 1/2H), 7.56 (d, J=7.2Hz, 1/2H), 7.38 (d, J=8.0Hz, 1/2H), 7.33 (d, J=7.5Hz, 1/2H), 7.14-7.01 (m, 3H), 5.44 (dd, J=6Hz, 8Hz, 1/2H), 4.30-4.10 (m, 5/2H), 3.92 (d, J=13.3Hz, 1/2H), 3.81 (d, J=13.3Hz, 1/2H), 3.67 (d, J=13.3Hz, 1/2H), 3.48-3.40 (m, 1/2H), and 3.28-3.09 (m, 7/2H), 2.55 (dt, 1/2H), and 2.26-2.20 (br.d, 1/2H), 2.05 (s, 3H), and 1.80-1.70 (m, 1/2H), 1.67,1.59,1.55,1.43 (4s, 6H), 1.27 (t, J=7.0Hz, 3/2H), 1.19 (t, J=7.0Hz, 3/2H), 0.90-0.85 (m, 1/2H) .d
1 1H NMR (CD
3OD, 400MHz): this chemical compound ratio is about two kinds of rotamers existence of 1: 1.δ 7.77 (d, J=7.5Hz, 1/2H), 7.56 (d, J=7.9Hz, 1/2H), and 7.35-7.30 (m, 1H), 7.13-6.98 (m, 3H), 5.53 (dd, J=5.5Hz, 8Hz, 1/2H), 5.24 (app.t, J=7Hz, 1/2H), 4.30 (br.d, J=14Hz, 1/2H), and 4.20-4.10 (m, 2H), 3.90-3.85 (m, 1/2H), 3.86 (d, J=13.2Hz, 1/2H), 3.70 (d, J=13.7Hz, 1/2H), 3.35-3.10 (m, 4H), and 2.30-2.20 (m, 1/2H), 2.12,2.04 (2s, 3H), 2.04-2.00 (m, 1/2H), 1.80-1.70 (m, 3/2H), 1.54,1.50,1.43,1.26 (4s, 6H), 1.23 (t, J=6.7Hz, 3H), 0.90-0.84 (m, 1/2H) .d1 FAB-MS value of calculation C
24H
34N
4O
4S:474; Measured value 475 (M+H) d2 FAB-MS value of calculation C
24H
34N
4O
4S:474; Measured value 475 (M+H)
According to establish above, as the program that exemplifies among example C4 steps A and the B prepared the table CIII in other listed intermediate.According to example C4 step C and D; Make intermediate 1 prepare final chemical compound.
Intermediate
JateProduct
Intermediate late product sequence number Y MF MF isomer
FAB-MS(M+1)??????????????FAB-MS(M+1)1????????PhS-???????????????????C
14H
19NO
2S????????????C
29H
36N
4O
4S?????????d1
266??????????????????????537??????????????????????d22????????BnS-???????????????????C
15H
21NO
2S????????????C
30H
38N
4O
4S?????????d1
280 551 d23 2-pyridine sulfenyl-C
13H
18N
2O
2S C
28H
35N
5O
4S RS
267??????????????????????538
To NaIO
4(316.5mg, 1.48mmol) add in the solution that is stirring in water (5ml) and ethanol (5ml) intermediate that makes from example C4 steps A (300mg, 0.99mmol).At room temperature this mixture was stirred 5 hours, concentrate then and remove ethanol.This material ethyl acetate extraction (2 * 10ml).The organic layer dried over mgso obtains this title compound (286mg, 90.5%) after concentrating.FAB-MS:C
14H
25NO
5S: value of calculation: 319; Measured value: 320 (M+H).
According to example C1, the described program of step C, (230g 0.72mmol) 25 minute makes (197mg, 100%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (10ml).FAB-MS:C
9H
17NO
3S: value of calculation: 219; Measured value: 220 (M+H).
According to example C1, the described program of step D, the intermediate that makes by preceding step (140mg, 0.547mmol), intermediate 1 (1 equivalent), HOBT (1 equivalent), N-methylmorpholine (1 equivalent), and EDC (210mg, 1.094mmol) preparation.Obtain the non-enantiomer mixture (177mg, 55%) of this chemical compound with the purification of MPLC method.FAB-MS:C
29H
42N
4O
7S: value of calculation: 590; Measured value: 591 (M+H).
Step D:
According to example C1, the described program of step C, (150mg 0.254mmol) 20 minute makes (118mg, 90%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (10ml).FAB-MS:C
24H
34N
4O
5S: value of calculation: 490; Measured value: 491 (M+H).
Steps A:
With example C4, (300mg, (oxone, 910mg is 1.48mmol) in the mixture that is stirring in water (5ml) and methanol (5ml) 0.99mmol) to join Oxone for the intermediate that steps A makes.At room temperature this mixture was stirred 4 hours, concentrate then and remove methanol.Residue ethyl acetate extraction (2 * 10ml).The organic layer dried over mgso obtains title compound (321mg, 97%) after concentrating.FAB-MS:C
14H
25NO
6S: value of calculation: 335: measured value: 336 (M+H) [actual measurement 236 (M-t-Boc)].
Step B:
According to example C1, the described program of step C, (221mg 0.66mmol) 25 minute makes (192mg, 99%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (10ml).FAB-MS:C
9H
17NO
4S: value of calculation: 235; Measured value: 236 (M+H).
According to example C1, the described program of step D, the intermediate that makes by preceding step (140mg, 0.515mmol), intermediate 1 (1 equivalent), HOBT (1 equivalent), N-methylmorpholine (1 equivalent), and EDC (197mg, 1.03mmol) preparation.Obtain the non-enantiomer mixture (251mg, 80%) of chemical compound with the purification of MPLC method.FAB-MS:C
29H
42N
4O
8S: value of calculation: 606; Measured value: 607 (M+H).
Step D:
According to example C1, the described program of step C, (210mg 0.317mmol) 30 minute prepares (193mg, 98.5%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (10ml).FAB-MS:C
24H
34N
4O
8S: value of calculation: 506: measured value: 507 (M+H).
Example C7
Steps A:
At-78 ℃, under argon shield with KHMDS (0.5M, in toluene, 298ml, (50g is 0.196mol) in the solution that is stirring in THF (600ml) 0.298mol) to join the N-t-Boc-3-piperidine ethyl formate in 30 minutes.At-78 ℃, with this solution restir 30 minutes.Simultaneously, the suspension in dichloromethane with 3N NaOH and brinish mixture washing 2-pyrmethyl chloride hydrochlorate (25g) is to remove hydrochlorate.Organic layer MgSO
4Drying obtains brown oil after the evaporation, then it is joined in above-mentioned-78 ℃ solution at leisure.The reactant mixture stirring is spent the night, make it be warmed to room temperature.This material is concentrated, and dilute with water is used ethyl acetate extraction then.Organic layer anhydrous magnesium sulfate drying, filtration and concentrated.Dodging chromatograph with silicagel column and purify, is the hexane solution eluting of 20-80% ethyl acetate with the solvent gradient, obtains title compound (54.8g, 80%).
1H NMR (CD
3OD, 400MHz) δ 8.45 (dd, J=1.5Hz, 5Hz, 1H), 7.52 (app dt, J=2Hz, 8Hz, 1H), 7.07 (dd, J=5Hz, 6.6Hz, 1H), 7.05 (d, J=8Hz, 1H), 4.09-4.04 (br.m, 2H), 3.92 (br.d, 1H), 3.46 (br.m, 1H), 3.30-3.10 (br.m, 1H), 3.06 (d, J=13.7Hz, 1H), 2.95 (d, J=13.7Hz, 1H), 2.01-1.91 (br.m, 1H), 1.63-1.50 (br.m, 3H), 1.36 (v.br.s, 9H), 1.13 (t, 7.1Hz, 3H) .FAB-MS:C
19H
28N
2O
4: value of calculation: 348; Measured value: 349 (M+H).
According to example C1, the described program of step C, (6.36g 18.2mmol) 45 minute makes (6.10g, 100%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (100ml).FAB-MS:C
14H
20N
2O
2: value of calculation: 248; Measured value: 249 (M+H).
According to example C1, the described program of step D, by the chemical compound of preceding step preparation (500mg, 1.556mmol), intermediate 1 (1 equivalent), HOBT (1 equivalent), N-methylmorpholine (2 equivalent), and EDC (597mg, 3.11mmol) preparation.Purify with the MPLC method, obtain title compound (883mg, 91.5%) with eluent ethyl acetate.FAB-MS:C
34H
45N
5O
8: value of calculation: 619; Measured value: 620 (M+H).
Step D:
According to example C1, the described program of step C, (250g 0.404mmol) 25 minute prepares (204mg, 85%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (25ml).FAB-MS:C
29H
37N
5O
4: value of calculation: 519; Measured value: 520 (M+H).
According to what establish above, other listed intermediate among the table CIV have been prepared as the program that exemplifies among example C7 steps A and the B.According to example C7 step C and D, prepared final chemical compound with intermediate 1.
Table CIV
Midbody product
Midbody product sequence number Y MF MF isomer
FAB-MS (M+1) FAB-MS (M+1) 1 3-picolyl C
14H
20N
2O
2C
29H
37N
5O
4RS
249 5202 4-picolyl C
14H
20N
2O
2C
29H
37N
5O
4RS
249 5203 2-quinoline methyl C
18H
22N
2O
2C
33H
39N
5O
4RS
According to example C7 step C and D, replace intermediate 1 to prepare other listed chemical compounds among the table CIVa with some listed among table CIV intermediate and intermediate 3.
FAB-MS (M+1) 1 2-picolyl C29H40N4O4 d1
509 d22 3-picolyl C29H40N4O4 d1
509 d23 4-picolyl C29H40N4O4 d1
Example C8
Steps A:
According to example C1, the described program of step D is by example C7, intermediate (the 6g that step B makes, 18.67mmol) and with (R)-(-)-(O)-acetyl mandelic acid (1 equivalent), HOBT (1 equivalent), N-methylmorpholine (2 equivalent), and EDC (7.16g, 37.34mmol) preparation.Purify with the MPLC method,, obtain two kinds of enantiopure compound with 80% ethyl acetate and hexane solution eluting.The isomer of coming out from chromatographic column earlier is designated as d
1(3.92g, 99%), the isomer of coming out from chromatographic column in the back is designated as d
2(3.69g, 93%).
FAB-MS:C
24H
28N
2O
5: value of calculation: measured value: 425.Intermediate d
1Structure measure with X-radiocrystallgraphy method.After providing the absolute stereo chemistry of (R)-O-acetyl mandelic acid, the spatial chemistry on the piperidines 3-position is at d as can be known
1In be (S)-.
Step B:
The intermediate d that preceding step is made
1(2.91g 6.86mmol) refluxed 5 hours in ethanol (30ml) with dense HCl (25ml).With reactant mixture vacuum evaporation, residue is purified with the silica gel flash column chromatography, and be 1: 10: 90 ammonium hydroxide with the solvent gradient: methanol: the chloroform eluting obtains this chemical compound (d
1, 1.52g, 70%).
1H NMR (CD
3OD, 400MHz) δ 8.84 (app.d, J=6Hz, 1H), 8.60 (app.dt, J=1.5Hz, 8Hz, 1H), 8.04 (t, J=6Hz, 1H), 7.94 (d, J=8Hz, 1H), 4.34-4.27 (m, 1H), and 4.23-4.17 (m, 1H), 3.75 (d, J=13Hz, 1H), 3.46 (d, J=13.3Hz, 1H), 3.40 (d, J=13.3Hz, 1H), 3.31-3.29 (m, 2H), 3.20 (d, J=13Hz, 1H), 3.03 (app dt, J=3.1Hz, 12.8Hz, 1H), 2.24 (br.d, 1H), 2.00-1.93 (m, 1H), 1.88 (dd, J=3.7Hz, 13.5Hz, 1H), 1.63-1.60 (m, 1H), 1.23 (t, 7.1Hz, 3H) .FAB-MS:C
14H
20N
2O
2: value of calculation: 248; Measured value: 249 (M+H).
Step C:
According to example C1, the described program of step D is by the intermediate (d of this case step B preparation
1, 1.50g, 4.67mmol), N-t-Boc-D-Trp (1 equivalent), HOBT (1 equivalent) and EDC (1.53g, 8.00mmol) preparation.Purify with the MPLC method, use eluent ethyl acetate, obtained this chemical compound (1.74g, 71%).FAB-MS:C
30H
38N
4O
5: value of calculation: 534; Measured value: 535 (M+H).
Step D:
According to example C3, the described program of step C, (1.658g 3.11mmol) reacts 35 minute (1.56g, 99%) .FAB-MS:C in 0 ℃ with HCl gas to the intermediate that is prepared by preceding step in ethyl acetate (50mg)
25H
30N
4O
3: value of calculation: 434; Measured value: 435 (M+H).
Step e:
According to example C1, the described program of step D, the intermediate (1.5g that makes by this case step D, 2.96mmol), N-t-Boc-Alpha-Methyl alanine (1.1 equivalent), DMAP (0.15 equivalent), N-methylmorpholine (1 equivalent), and EDC (1.135g, 5.92mmol) preparation.Obtain title compound (1.488g, 81%) with the purification of MPLC method.FAB-MS:C
34H
45N
5O
6: value of calculation: 619; Measured value: 620 (M+H).
Step F:
According to example C1, the described program of step C, (1.40g 2.26mmol) 1 hour makes (1.388g, 100%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by step e in ethyl acetate (100ml).1H NMR (CD
3OD, 400MHz): 8.79-8.78 (M, 1H), 8.56-8.48 (M, 24), and 8.0-7.96 (M, 1H), 7.72 (d, J=8.21Hz, 1H) 7.53 (d, J=7.98, Hz, 1H) 7.25-7.22 (M, 2H) 6.89-6.86 (M, 1H) 5.48-5.43 (M, 1H) 3.89 (1, J=7.1Hz, 2H) 2.30 (d, J=14.3Hz, 1H) 1.85 (d, J=14.4Hz, 1H) 1.01 (t, J=7.1Hz, 3H) 3H) FAB-MS:C
29H
37N
5O
4: value of calculation: 519; Measured value: 520 (M+H).
Similarly, by example 8, the intermediate d that steps A obtains
2Make title compound.FAB-MS:C
29H
37N
5O
4: value of calculation: 519; Measured value: 520 (M+H).
Example C10
To nipecotic acid (5g, 38.7mmol) add in the solution that is stirring in NaOH (2 equivalent) aqueous solution two dimethyl dicarbonate butyl esters (10g, 46.44mmol).At room temperature this mixture was stirred 2 days.Then it slowly is acidified to pH=3, restir 2 hours.This solution obtains white solid (6.25g, 70%) with ethyl acetate extraction, drying and concentrated.
Step B:
With EDC (6.9g, 35.4mmol) join the intermediate that preceding step makes (6.25g, 27.3mmol), benzyl alcohol (3.4ml, 32.7mmol) and DMAP (33mg is 0.273mmol) in the solution in 0 ℃ of dichloromethane.At room temperature reactant mixture was stirred 7 hours.This mixture washs, uses anhydrous magnesium sulfate drying, filtration with the mixture of saline and 3N HCl and concentrates.Purifying with the silica gel flash column chromatography, is the ethyl acetate isohexane eluant solution of 10-30% with gradient, obtains this benzyl ester (7.41g, 85%).
According to example C1, the described program of step B, by N-t-Boc-3-piperidine carboxylic acid benzyl ester (7.12g, 22.2mmol), the THF solution of LHMDS (33.3ml, 33.3mmol) and benzyl bromide a-bromotoluene (4.0g, 33.3mmol).Purify with the silica gel flash column chromatography,, obtain title compound (9.10g, 100%) with 5-20% ethyl acetate and hexane solution eluting.
1H?NMR(CDCl
3,400MHz)δ7.33-7.28(m,3H),7.23-7.17(m,5H),7.01-6.98(m,2H),5.00(br.ABq,JAB=12Hz,2H),4.00(br.s,1H),3.55-3.50(m,1H),3.18(d,J=13Hz)3.14(v.br.s,1H),2.92(d,J=13.5Hz),2.74(d,J=13.4Hz),2.03-1.99(m,1H),1.63-1.50(m,3H),1.39(s,9H).
According to example C1, the described program of step C, (3.08g 7.52mmol) 15 minute makes (2.65g, 100%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (40ml).FAB-MS:C
20H
23NO
2: value of calculation: 309; Measured value: 310 (M+H).
According to example C1, the described program of step D, by the intermediate of preceding step preparation (768mg, 2.22mmol), intermediate 1 (720mg, 1.85mmol), HOBT (1 equivalent), N-methylmorpholine (1 equivalent), and EDC (2 equivalent) preparation.Purify with the MPLC method,, obtain two kinds of diastereomers with 50% ethyl acetate and hexane solution eluting.The isomer that washes out earlier is designated as d
1(504mg, 40%), after the isomer that washes out be designated as d
2(474mg, 38%).d
1FAB-MS:C
40H
48N
4O
6: value of calculation: 680; Measured value: 681 (M+H).d
2FAB-MS:C
40H
48N
4O
6: value of calculation: 680; Measured value: 681 (M+H).
Step F:
According to example C1, the described program of step C, (25mg 0.036mmol) 10 minute makes (20.2mg, 91%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by step e in ethyl acetate (3ml).FAB-MS:C
35H
40N
4O
4: value of calculation: 580; Measured value: 581 (M+H).
According to example C1, the described program of step C, by example C10, the intermediate d of step e
2(20.1mg 0.03mmol) 10 minute makes (12.8mg, 70%) in 0 ℃ of reaction with HCl gas in ethyl acetate (3ml).FAB-MS:C
35H
40N
4O
4: value of calculation: 580: measured value: 581 (M+H).
Example C12
10% carbon is carried palladium (60mg) and example C10, the intermediate (d that step e makes
1) (442.6mg, 0.65mmol) the fierce stirring 30 minutes under nitrogen atmosphere of the suspension in ethanol (20ml).Then reactant mixture is passed through diatomite filtration, obtain product (376.0mg, 98%) after the evaporation.d
1FAB-MS:C
33H
42N
4O
6: value of calculation: 590; Measured value: 591 (M+H).
According to example C1, the described program of step C, (211mg 0.357mmol) 10 minute makes (175.6mg, 93%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (15ml).
1H NMR (CD
3OD, 400MHz): this chemical compound exists with two kinds of rotamer forms, and its ratio is about 1: 1.δ 7.57-7.54 (m, 1H), 7.38 (d, J=8.2Hz, 1/2H), 7.33 (d, J=8.2Hz, 1/2H), 7.25-7.00 (m, 8H), 6.81-6.79 (m, 1H), 5.36 (dd, J=6Hz, 8.5Hz, 1/2H), 5.18 (appt, J=7.5Hz, 1/2H), 4.32 (br.d, J=13Hz, 1/2H), 4.00 (br.d, J=13Hz, 1/2H), 3.78 (br.d, J=13Hz, 1/2H), 3.26-3.02 (m, 11/2H), 2.86 (d, J=13.4Hz, 1/2H), 2.80 (d, J=13.4Hz, 1/2H), 2.53 (d, J=13.4Hz, 1/2H), 2.46 (d, J=13.4Hz, 1/2H), 2.29 (dt, 1/2H), 2.09 (d, J=12.7Hz, 1/2H), 1.92-1.88 (m, 1/2H), 1.55,1.50,1.44 (3s, 6H), 1.40-1.25 (m, 1H), 1.20-1.12 (m, 1/2H) .d
1FAB-MS:C
28H
34N
4O
4: value of calculation: 490; Measured value: 491 (M+H).
Similarly by example C10, the intermediate d that step e obtains
2(224.2mg 0.33mmol) makes (169.3mg, 87%).d
2FAB-MS:C
33H
42N
4O
6: value of calculation: 590: measured value: 591 (M+H).
According to example C1, the described program of step C, (139mg 0.235mmol) 10 minute makes (122.7mg, 99%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (15ml).
1H NMR (CD
3OD, 400MHz): this chemical compound exists with two kinds of rotamer forms, and its ratio is about 1: 1.δ 8.21 (d, J=7.4Hz, 1/2H), 7.91 (d, J=7.4Hz, 1/2H), 7.62 (d, J=7.9Hz, 1/2H), 7.50 (d, J=7.9Hz, 1/2H), 7.34-6.90 (m, 9H), 5.40-5.34 (m, 1H), 4.40 (d, J=13.7Hz, 1/2H), 4.13 (d.J=12.6Hz, 1/2H), 3.63 (d, J=13.3Hz, 1/2H), 3.50 (d, J=13.3Hz, 1/2H), 3.30-3.10 (m, 7/2H), 2.93 (ABq, 1H), 2.88 (v.br.d, 1/2H), 2.60 (d, J=13Hz, 1/2H), 2.40 (d, J=13Hz, 1/2H), and 2.19-2.16 (m, 1/2H), 1.78-1.75 (m, 1H), and 1.60-1.40 (m, 3/2H), 1.20-1.10 (m, 1/2H), 1.58,1.50,1.47,1.15 (4s, 6H), 1.00-0.90 (m, 1/2H) .d
2FAB-MS:C
28H
34N
4O
4: value of calculation: 490; Measured value: 491 (M+H).
According to example C10 to C12, the intermediate that obtains with intermediate 3 and example C10 step D has made other listed examples among the table CV.
Table CV: additional example
Sequence number X MF isomer
FAB-MS(M+1)1????CO2Bn??????C35H43N3O4??????RS
5702????CO2H???????C28H37N3O4??????RS
480
(4.9ml 12.36mmol) joins 2,2,6, and (1.92g 13.5mmol) in the solution that is stirring in THF (25ml), cools off with ice bath the 6-tetramethyl piperidine simultaneously for TMP, 2.3ml with n-BuLi and hexane solution.With the benzyl of the N-t-Boc-3-in another flask-nipecotic acid ethyl ester (example C1, step B, 1.73g, 5mmol) and CH
2Br
2(12.4mmol) stirring the mixture in THF (20ml) is cooled to-78 ℃ for 0.78ml, 2.15g, is being lower than then to add the lithium salt solution of the TMP solution of preparation just under-65 ℃ the temperature in 15 minutes.After 10 minutes ,-78 ℃ in 10 minutes, add the LHMDS solution (11.2ml, 11.2mmol).After interpolation finishes, remove cooling bath, allow mixture be warmed to 0 ℃ gradually.Cool off this mixture with ice bath, be lower than under 5 ℃ the temperature with about 15 minutes clock times add n-BuLi hexane solution (13.5ml, 33.7mmol).Allow mixture be warmed to room temperature, and stirred 45 minutes.This mixture is cooled to-78 ℃,, makes it about 50 minutes clock times of quenching by it being joined in acidic ethanol (30ml) solution that is stirring 0 ℃.This mixture is evaporated to dried, makes it then to be suspended in the dichloromethane (100ml), to wherein add triethylamine (0.7ml, 5.0mmol) and Bis(tert-butoxycarbonyl)oxide (1.09g 5.0mmol), stirs simultaneously.After at room temperature stirring 1 hour, the salt water washing of this material, drying and concentrated.Purify with the silica gel flash column chromatography, the hexane solution eluting with the 10-30% ethyl acetate obtains this chemical compound (1.44g, 80%).
According to example C1, the described program of step C, (1.30g 3.56mmol) 45 minute makes (975mg, 91%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (50ml).FAB-MS:C
16H
23NO
2: value of calculation: 261; Measured value: 262 (M+H).
Step C:
According to example C1, the described program of step D, by the intermediate of preceding step preparation (55g, 0.21mmol), intermediate 1 (1 equivalent), HOBT (1 equivalent), N-methylmorpholine (1 equivalent), and EDC (80mg, 0.42mmol) preparation.Purify with the MPLC method,, obtain this chemical compound (77mg, 61.5%) with the hexane solution eluting of 60% ethyl acetate.
According to example C1, the described program of step C, (77mg 0.13mmol) 15 minute makes (59mg, 85%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (8ml).FAB-MS:C
31H
40N
4O
4: value of calculation: 532: measured value: 533 (M+H).
(1.85g is 4.52mmol) at 1 atmospheric pressure H with intermediate that the step C of example C10 makes
2Pressure and 10% carbon carry in palladium (150mg) ethanol (20ml) mixture and carry out hydrogenation.By obtaining described acid (1.36g, 94%) after diatomite filtration and the evaporation.
1H NMR (CDCl
3, 400MHz) δ 7.27-7.19 (m, 3H), 7.14-7.10 (m, 2H), and 4.08-3.59 (br.m, 1H), 3.63-3.59 (m, 1H), and 3.15-3.05 (br.m, 2H), 2.9. (d, J=13.5Hz, 1H), 2.79 (d, J=13.5Hz, 1H), and 2.05-1.95 (br.m, 1H), 1.70-1.45 (m, 3H), 1.42 (s, 9H) .EI-MS: value of calculation: C
18H
25NO
4: 319; Measured value: 319 (M
+).
Step B:
Contain ethylamine hydrochloride (163mg, 2.0mmol), DMAP (1.0 equivalent), and the intermediate that makes by preceding step of N-methylmorpholine (2 equivalent) (320.4mg 1.0mmol) adds EDC (2 equivalent) in the solution in dichloromethane.Reactant mixture is in stirred overnight at room temperature.This solution is used anhydrous magnesium sulfate drying with 3N HCl and salt water washing, filters then, concentrates.Dodge 60-100% ethyl acetate gradient elution in the chromatographic grade hexane through silicagel column, obtain title compound (262mg, 76%) after the purification.
1H NMR (CDCl
3, 400MHz) δ 7.21-7.13 (m, 3H), 7.03 (d, 2H), 6.68 (br.s, 1H), 4.18 (br.d, 1H), 3.96 (br.d, 1H), 3.12-3.00 (m, 4H), and 2.70-2.40 (br.m, 5H), 1.60-1.50 (m, 1H), 1.37 (s, 9H), 1.20-1.30 (m, 1H), 0.90 (q, J=7.3Hz, 3H) .EI-MS: value of calculation: C
20H
30N
2O
3: 346; Measured value: 346 (M
+).
Press the described program of example C1 step C, (262mg 0.76mmol) 1 hour makes (194mg, 90%) 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (5ml).
1H?NMR(CD
3OD,400MHz)δ8.28(br.s,1H),7.30-7.24(m,3H),7.14-7.12(m,2H),3.43(d,J=12Hz,1H),3.34-3.28(m,2H),3.26-3.20(br.d,1H),3.11(d,J=14Hz,1H),2.88(dt,J=3.2Hz,13Hz,1H),2.81(d,J=12.5Hz,1H),2.77(d,J=14Hz,1H),2.24(d,J=13Hz,1H),1.87(td,J=2.8Hz,14Hz,1H),1.75(dt,J=3.3Hz,13.5Hz,1H),1.64-1.55(m,1H),1.17(t,J=7Hz,3H).
Step D:
Press the described program of example C1 step D, and the intermediate that makes by preceding step (62.2mg, 0.22mmol), intermediate 1 (1 equivalent), HOBT (1 equivalent), N-methylmorpholine (1 equivalent) and EDC (2 equivalent) make.By the MPLC method, use eluent ethyl acetate, obtain two kinds of diastereomers after the purification, a kind of d of being designated as that from post, washes out earlier
1(35.8mg, 26%), after a kind of d of being designated as of washing out
2(43.8mg, 31%).d
2.
1H NMR (CD
3OD, 400MHz): this chemical compound exists with two kinds of rotamers, and its ratio is about 1: 1.δ 8.16 (br.s, 1/2H), 7.53 (d, J=8.7Hz, 1H), 7.32 (d, J=8.1Hz, 1H), 7.25-6.96 (m, 8H), 6.69 (br.s, 1/2H), 5.28-5.12 (m, 1/2H), 4.94 (v.br.m, 1/2H), 4.31 (br.d, J=14.6Hz, 1/2H), 3.49 (v.br.d, J=13Hz, 1/2H), 3.22 (dd, J=4.7Hz, 14.3Hz, 1/2H), and 3.03-2.97 (m, 2H), 2.90 (d, J=13.4Hz, 1/2H), 2.40 (br.d, 1/2H), 2.36 (d, J=13.3Hz, 1/2H), 2.10 (d, J=13.5Hz, 1/2H), 1.92-1.82 (br.m, 3/2H), 1.47 (s, 3H), 1.41 (s, 9H), 1.38 (s, 3H), 1.32-1.20 (m), 1.10-1.00 (dt, 1/2H), 0.85 (t, J=7.2Hz, 3H) .d
1FAB-MS value of calculation: C
35H
47N
5O
5: 617; Measured value: 618 (M+H) d
2FAB-MS value of calculation: C
35H
47N
5O
5: 617; Measured value: 618 (M+H)
Step e:
Press the described program of example C1 step C, the intermediate d that obtains by preceding step
1(35mg, 0.057mmol) and HCl gas in ethyl acetate (3ml), made (32.5mg, 100%) in 30 minutes 0 ℃ of reaction.FAB-MS value of calculation: C
30H
39N
5O
3: 517; Measured value: 518 (M+H).
Press the described program of example C1 step C, (41mg 0.066mmol) 30 minute makes (36.5mg, 100%) 0 ℃ of reaction with HCl gas to the intermediate that is obtained by example C15 step D in ethyl acetate (3ml).
1H NMR (CD
3OD, 400MHz): this chemical compound exists with two kinds of rotamers, and its ratio is about 4: 1.δ 8.21 (d, J=7.4Hz, 4/5H), 8.02 (d, J=7.4Hz, 1/5H), 7.68 (d, J=7.8Hz, 1/5H), 7.54 (d, J=7.8Hz, 4/5H), 7.35 (d, J=7.1Hz, 4/5H), 7.31 (d, J=7.1Hz, 1/5H), 7.26-6.98 (m, 8H), 5.46-5.40 (m, 1/5H), 5.25-5.20 (m, 4/5H), 4.00 (br.d, 4/5H), 3.85 (br.d, 1/5H), 3.65 (br.d, J=13.2Hz, 4/5H), 3.60-3.54 (m, 1/5H), 3.36 (br.d, 1/5H), 3.30-3.03 (m), 2.99-2.90 (m), 2.82-2.62 (m), 2.46 (d, J=13.3Hz, 8/5H), 2.08 (br.d, 4/5H), 1.90-1.84 (m, 1/5H), 1.76-1.65 (m), 1.51,1.49 (2s, 6H), 1.40-1.20 (m), 1.00 (t, J=7.2Hz, 3/5H), 0.88 (t, J=7.2Hz, 12/5H) .FAB-MS value of calculation: C
30H
39N
5O
3: 517: measured value: 518 (M+H).
Example C17
Bis(tert-butoxycarbonyl)oxide (18g, 1.2 equivalents) is joined the S-isomer intermediate of example C2 steps A at leisure, and (27.3g is 68.8mmol) in the suspension in 3N sodium hydroxide (25ml), dichloromethane (200ml) and water (100ml).Add finish after with this mixture restir 5 hours, be acidified to pH3 carefully, use ethyl acetate extraction then 3 times.With organic extract merging, dry, also concentrated, obtain white solid thing (23.7g).(11.5g 33.1mmol) refluxed 1 day with the solution of 3N NaOH (30ml) in ethanol (200ml) and water (10ml) with this intermediate.This solution evaporation is removed ethanol, be acidified to pH=3 with 3N HCl then, the reuse ethyl acetate extraction.With extract drying, evaporation, purify by short silicagel column then, originally use the hexane solution eluting of 20% ethyl acetate, use eluent ethyl acetate then, obtain this product (8.76g, 83%).NMR is identical with example C15 steps A with the MS data.
With EDC join the intermediate that obtains by preceding step (660mg, 2.07mmol), ethylamine hydrochloride (251mg, 1.5 equivalents), NMM (0.23ml, 1 equivalent) and HOBT (1 equivalent) dichloromethane and DMF (1: 1,10ml) in the mixture in.This mixture was stirring at room 2 days, and reflux 2 hours is poured in rare HCl and the brinish mixture then.Use ethyl acetate extraction, organic layer washs with rare NaOH, dry and evaporation.Purify by dodging chromatographic column, obtain this product (540mg, 75%) behind the ethyl acetate isohexane eluant solution with 20-80%.NMR is identical with example C15 step B with MS.
Step C:
Press the described program of example C1 step C, (0.33g 0.95mmol) made (0.279mg, 100%) in 15 minutes in 0 ℃ of reaction to the intermediate that is made by preceding step in ethyl acetate (5ml) and HCl gas.FAB-MS: value of calculation: C
15H
22N
2O:246; Measured value: 247 (M+H).
Press the described program of example C1 step D, by the intermediate of preceding step preparation (100mg, 0.354mmol), intermediate 3 (134mg, 0.354mmol), HOBT (48mg, 1 equivalent), N-methylmorpholine (0.039ml, 1 equivalent) and EDC (102mg, 1.5 equivalents) preparation.Purify by the MPLC method, use eluent ethyl acetate, obtain this intermediate (140mg, 65%).FAB-MS: value of calculation: C
35H
50N
4O
6: 606: measured value: 607 (M+H).
Press the described program of C1 step C, (132mg 0.217mmol) 10 minute makes (113.3mg, 96%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (5ml).d
1FAB-MS: value of calculation: C
30H
42N
4O
3: 506: measured value: 507 (M+H).
The program that listed other intermediate is determined by the front among the table CVIa prepares as example C15 and example C17 steps A to the program that C exemplified.Final chemical compound is according to example C17 step D and E, with intermediate 1 preparation.
Midbody product
Midbody product sequence number X MF MF isomer
FAB-MS (M+1) FAB-MS (M+1) 1-CO (morpholino) C
17H
24N
2O
2C
32H
41N
5O
4S
288(M
+,EI)??????5602?????-CONHCH
3?????????C
14H
20N
2O?????C
29H
37N
5O
3????S
233???????????????5043?????-CONH-????????????C
17H
24N
2O
3???C
32H
41N
5O
5????S
CH
2CO
2Et???????304(M
+,EI)??????5764?????-CO
2CH
2CO
2Et??C
17H
23NO
4?????C
32H
40N
4O
6????R
306???????????????577???????????????S5?????-CO
2(CH
2)
2SMe?C
16H
23NO
2S????C
31H
40N
4O
4S???R
294???????????????565???????????????S6?????-CON(CH3)2????????C15H22N2O?????????C30H39N5O3????????d1
247???????????????518???????????????d27?????-CONH-????????????C
15H
22N
2O
2????C
30H
39N
5O
4???S
(CH
2)
2OH?????????263???????????????534
Similarly, with 3-aminopropanol or 2-(ethylmercapto group) ethamine, use intermediate 1 can prepare the chemical compound shown in the table CVIb.
Sequence number X
1???????-CONH(CH
2)
3OH
2-CONHCH
2CH
2SCH
3Other listed chemical compounds are pressed example 17 step C and D among the table CVIc, prepare with listed some intermediate and intermediate 3 among the table CVIa.
Sequence number Y MF isomer
FAB-MS(M+1)
1-CO (morpholino) C
32H
44N
4O
4S
549
2?????-CONHCH
3?????C
29H
40N
4O
3????S
493
3????-CONH-??????C
32H
44N
4O
5????S
CH
2CO
2Et??565
4????-CONH-??????C
30H
42N
4O
4????S
CH
2)
2OH???523
Similarly, with 3-aminopropanol and 2-(methyl mercapto)-ethamine, can prepare listed chemical compound among the table CVId.
Sequence number X
1?????-CONH(CH
2)
3OH
2?????-CONHCH
2CH
2SCH
3
Other listed chemical compounds are pressed example 17 step C and D among the table CVIe, prepare with listed some intermediate and intermediate 2 among the table CVI.
FAB-MS (M+1) 1-CO (morpholino) C
31H
42N
4O
5S
5512????-CONHCH
3??????C
28H
38N
4O
4????S
4953????-CONH-?????????C
31H
42N
4O
6????S
CH
2CO
2Et?????567
Example C18
(1M, (10.4g is in dichloromethane 29.93mmol) (100ml) solution 45ml) to join the N-t-Boc-3-benzyl-nipecotic acid ethyl ester that is stirring with DIBAL at-78 ℃.Reactant mixture stirred 4 hours at-78 ℃, added methanol (5ml) then and made the stopping of reaction.Reactant mixture carefully washs with aqueous tartaric acid solution and saline, uses MgSO
4Drying, evaporation then.Carrying out silica gel and dodge the chromatograph purification, is the ethyl acetate isohexane eluant solution of 40-80% with gradient, obtains this product (6.81g, 75%).EI-MS: value of calculation: C
18H
27NO
3: 305; Measured value: 305 (M
+).
(770mg, 2.52mmol) solution in ethanol (20ml) and concentrated hydrochloric acid (1ml) refluxed 3 hours the intermediate that preceding step is made.Reactant mixture is cooled to room temperature, and solid title compound obtains being white in color after evaporation.(609.0mg,100%)。
1H NMR (CD
3OD, 400MHz) δ 7.31-7.19 (m, 5H), 3.45 (ABq, J=11Hz, 2H), 3.18 (d, J=13Hz, 1H), and 3.19-3.13 (m, 1H), 3.03-2.99 (m, 1H), 2.96 (d, J=13Hz, 1H), 2.72 (s, 1H), 1.92-1.84 (m, 2H), 1.60-1.50 (m, 2H) .EI-MS: value of calculation: C
12H
17NO:191; Measured value: 191 (M
+).
Press example C1, the program of step D, the intermediate that obtains by preceding step (142mg, 0.587mmol), intermediate 1 (0.8 equivalent), HOBT (1 equivalent), N-methylmorpholine (1 equivalent) and EDC (2 equivalent) preparation.Purify by the MPLC method, obtain two kinds of chemical compounds with eluent ethyl acetate, the chemical compound that comes out from pillar earlier is designated as d
1(98.5mg, 58%), the chemical compound that comes out from pillar in the back is designated as d
2(34.5mg, 12%).d
1FAB-MS: value of calculation: C
32H
42N
4O
5: 562: measured value: 563 (M+H).d
2FAB-MS: value of calculation: C
32H
42N
4O
5: 562; Measured value: 563 (M+H).
Intermediate (the d that obtains from preceding step
1) (60mg 0.104mmol) uses HCl gas treatment 5 minutes at 0 ℃ in ethyl acetate (3ml).Obtain the diastereomer 1 of this title compound after the evaporation.d
1FAB-MS: value of calculation: C
28H
36N
4O
3: 476: measured value: 477 (M+H).
Intermediate (the d that obtains from step C
2) (20mg) in ethyl acetate (3ml), use HCl gas treatment 5 minutes at 0 ℃.Obtain the diastereomer 2 of this title compound after the evaporation.d
2FAB-MS: value of calculation: C
28H
36N
4O
3: 476: measured value: 477 (M+H).
At 0 ℃ mesyl chloride (1.95ml) is joined by example C18, (5.12g is 16.8mmol) and in the solution that is stirring of triethylamine (4.7ml) in dichloromethane for the intermediate that steps A makes.Reactant mixture was stirred 2 hours.This solution is poured in the mixture of saline and 3NHCl, uses ethyl acetate extraction then.Organic layer obtains methanesulfonates with saturated sodium bicarbonate washing dried over mgso after evaporation.(2.2g 33.6mmol) heated for 2 weeks in 80 ℃ together in DMSO (20ml) for this methanesulfonates and Hydrazoic acid,sodium salt.This mixture is poured in the frozen water, uses ethyl acetate extraction then.Organic layer carries out drying and evaporation then with saturated sodium bicarbonate and salt water washing.Obtain azide (4.14g, 75%) through the purification of silica gel flash column chromatography.
1H NMR (CDCl
3, 200MHz) δ 7.29-7.13 (m, 5H), 3.61-3.57 (br.m.1H), 3.47 (d, J=12Hz, 1H), 3.20-3.10 (v.br.s, 2H), 3.10-2.96 (v.br.d, 1H), and 2.60-2.45 (br.m, 2H), 1.65-1.48 (m, 4H), 1.44 (s, 9H), 1.41-1.35 (m, 1H) .FAB-MS: value of calculation: C
18H
26N
4O
2: 330; Measured value: 331 (M+H).
Step C:
(1.60g 4.84mmol) carries palladium (160mg) catalyst in ethanol (25ml) with 10% carbon to the azide that obtains from preceding step, carries out hydrogenation 2 hours under 1 atmospheric pressure hydrogen atmospheric pressure.Reactant mixture by diatomite filtration, is obtained amine (1.42g, 96%) after the evaporation.FAB-MS: value of calculation: C
18H
28N
2O
2: 304; Measured value: 305 (M+H).
(0.73ml, (1.30g, 4.27mmol) in the solution that is stirring in dichloromethane (20ml), this solution also contains DMAP (20mg) and triethylamine (1ml) 5.12mmol) to join the amine that is obtained by preceding step with CbzCl at 0 ℃.This reactant mixture was stirred 2 hours.This solution is poured in the mixture of saline and 3N HCl, uses ethyl acetate extraction then.Organic layer washs with saturated sodium bicarbonate, uses dried over mgso, and the residue that obtains after evaporation is purified by dodging chromatograph, with the hexane solution eluting of 20% ethyl acetate, obtains product (1.52g).FAB-MS: value of calculation: C
26H
34N
2O
4: 438; Measured value: 439 (M+H).
(1.50g is 3.42mmol) in the solution that is stirring in ethyl acetate (50ml), till saturated at 0 ℃ HCl gas bubbling to be entered into the intermediate that is obtained by preceding step.Reactant mixture was stirred 1 hour, obtain salt (1.32g, 100%) after the evaporation.
1H NMR (CD
3OD, 400MHz) δ 7.40-7.18 (m, 10H), 5.14 (s, 2H), 3.43,3.42 (2d, J=14.8Hz, 1H), 3.23 (td, J=4Hz, 12.1Hz, 1H), 3.00 (d, J=13Hz, 1H), 2.94 (d, J=14.7Hz, 1H), 2.83 (dt, J=3.4Hz, 12Hz, 1H), 2.74 (d, J=13Hz, 1H), 2.68 (d, J=13.6Hz, 1H), 2.62 (d, J=13.6Hz, 1H), 2.00-1.90 (m, 1H), 1.92-1.88 (m, 1H), 1.59-1.52 (m, 1H), 1.47-1.44 (m, 1H) .FAB-MS: value of calculation: C
21H
26N
2O
2: 338; Measured value: 339 (M+H).
Step F:
According to example C1, the described program of step D, the intermediate that makes by preceding step (1.00g, 2.67mmol), intermediate 1 (1.04g, 1 equivalent), HOBT (1 equivalent), N-methylmorpholine (2 equivalent) and EDC (820mg, 4.27mmol) preparation.Purify by the MPLC method,, obtain this chemical compound (1.54g, 81%) with the hexane solution eluting of 60% ethyl acetate.
(1.30g 1.83mmol) carries palladium (100mg) catalyst with 10% carbon and carry out hydrogenation in ethanol (15ml) under hydrogen balloon pressure the intermediate that is obtained by preceding step.Reactant mixture is by diatomite filtration, obtains amine (1.20g, 100%) after purified.FAB-MS: value of calculation: C
33H
45N
5O
4: 575: measured value: 576 (M+H).
0 ℃ with mesyl chloride (0.042ml) join the intermediate that makes by preceding step (286mg, 0.497mmol), in DMAP (10mg) and the solution that is stirring of N-methylmorpholine (0.109ml) in dichloromethane (10ml).Reactant mixture was stirred 2 hours.This solution is poured in the mixture of saline and 3N HCl, uses ethyl acetate extraction then.Organic layer washs with saturated sodium bicarbonate, uses dried over mgso, and the residue that obtains after evaporation is purified by dodging chromatograph, with the hexane solution eluting of 90% ethyl acetate, obtains product (285.9mg, 88%).FAB-MS: value of calculation: C
34H
47N
5O
6S:653; Measured value: 654 (M+H).
According to example C1, the described program of step C, (265mg 0.405mmol) 30 minute prepares (189mg, 79%) in 0 ℃ of reaction with HCl gas to the intermediate that is obtained by preceding step in ethyl acetate (8ml).FAB-MS: value of calculation: C
29H
39N
5O
4S:553; Measured value: 554 (M+H).
Example 20
According to example C1, the described program of step C, by example C19, (109mg 0.154mmol) 30 minute prepares (90mg, 90%) in 0 ℃ of reaction with HCl gas to the intermediate that step F obtains in ethyl acetate (4ml).FAB-MS: value of calculation: C
36H
43N
5O
4: 609: measured value: 610 (M+H).
With example C19, the intermediate that step G obtains (208mg, 0.362mmol) and the mixture of pyridine (2ml) and acetic anhydride (2ml) at 60 ℃ of heating 30 minutes, vaporising under vacuum then.Purify through MPLC,, obtain product (202mg, 90%) with the hexane solution eluting of 80% ethyl acetate.FAB-MS: value of calculation: C
35H
47N
5O
5: 617; Measured value: 618 (M+H).
Step B:
According to example C1, the described program of step C, (192mg 0.311mmol) 30 minute prepares (168.1mg, 98.5%) in 0 ℃ of reaction with HCl gas to the intermediate that is obtained by preceding step in ethyl acetate (4ml).FAB-MS: value of calculation: C
30H
39N
5O
3: 517; Measured value: 518 (M+H).
Example C22
Steps A:
With platinum oxide (IV) (200mg), the 3-Pyridineacetic Acid ethyl ester (5.0g, 30.3mmol) and the suspension of concentrated hydrochloric acid (10ml) in ethanol (50ml) under hydrogen balloon pressure, stir and spend the night.Mixture is by diatomite filtration, and the residue that obtains after the evaporation refluxed 30 minutes with anhydrous acidify ethanol.Obtain product (6.28g, 100%) after the evaporation.
1H?NMR(CD
3OD,400MHz)δ4.13(q,J=7.2Hz,2H),3.40(dd,J=3.5Hz,12Hz,1H),3.35(br.d,1H),2.90(br.t,1H),2.73(t,J=12Hz,1H),2.35(d,J=7.5Hz,2H),2.26-2.17(m?1H),1.96-1.80(br.m,2H),1.80-1.70(m,1H),1.37-1.26(m,1H),1.24(t,J=7.1Hz,3H).
According to example C1, the described program of step D, the intermediate that makes by preceding step (128mg, 0.617mmol), intermediate 1 (200mg, 0.514mmol), HOBT (1 equivalent), N-methylmorpholine (1 equivalent), and EDC (200mg) preparation.Purify through MPLC,, obtain this chemical compound (247mg, 89%) with the hexane solution eluting of 80% ethyl acetate.
Step C:
According to example C1, the described program of step C, (225mg 0.415mmol) 15 minute prepares (184mg, 100%) in 0 ℃ of reaction with HCl gas to the intermediate that is obtained by preceding step in ethyl acetate (5ml).FAB-MS: value of calculation: C
24H
34N
4O
4: 442: measured value: 443 (M+H).
Less (the d of polarity that obtains by example C8 steps A
1) (7.25g's intermediate 17.08mmol) refluxed 8 hours in ethanol (20ml) and 10N NaOH (8.5ml).Make this mixture cool to room temperature then, and slowly handle to pH=11 with 3N HCl.Add the solution in the Bis(tert-butoxycarbonyl)oxide Zai diox (20ml) in this solution that is stirring, stirred then 2 hours.Solution is acidified to pH4, is neutralized to pH7 then, use ethyl acetate extraction 3 times.With organic extract merging, drying, and evaporate, obtain white solid thing (6.80g).FAB-MS: value of calculation: C
17H
24N
2O
4: 320; Measured value: 321 (M+H).
Step B:
Add EDC (1.2 equivalent) in dichloromethane (100ml) solution of the intermediate (6.5g), benzyl alcohol (2 equivalent) and the DMAP (20mg) that obtain of step forward.This mixture stirring at room 3 days, is poured into rare NaHCO then
3In the solution.With ethyl acetate extraction 3 times, use MgSO
4Dry.Purifying by dodging chromatograph in the evaporation back, with the hexane solution eluting of 40% ethyl acetate, obtains desired product (6,53g, 78%) FAB-MS: value of calculation: C
24H
30N
2O
4: 410; Measured value: 411 (M+H); 311 (M
+-Boc (100)).
According to example C1, the described program of step C, (1.0g 2.44mmol) 15 minute prepares (935mg, 99%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethanol (40ml).FAB-MS: value of calculation: C
19H
22N
2O
2: 310: measured value: 311 (M+H).
Step D:
According to example C1, the described program of step C, the intermediate that makes by preceding step (800mg, 2.09mmol), intermediate 1 (812mg, 2.09mmol), HOBT (1 equivalent), N-methylmorpholine (1 equivalent) and EDC (2 equivalent) preparation.Purify by MPLC,, obtain this intermediate (1.10g, 77%) with the hexane solution eluting of 80% ethyl acetate.d
1FAB-MS: value of calculation: C
39H
47N
5O
6: 681; Measured value: 682 (M+H).
10% carbon carries intermediate (1.05g, 1.54mmol) the fierce stirring 30 minutes under hydrogen-pressure of the suspension in ethanol (20ml) that palladium (150mg) catalyst and preceding step obtain.Then this reactant mixture is passed through diatomite filtration, obtain product (828mg, 91%) after the evaporation.d
1FAB-MS: value of calculation: C
32H
41N
5O
6: 591; Measured value: 592 (M+H).
According to example C1, the described program of step C, (211mg 0.357mmol) 10 minute prepares (175.6mg, 93%) in 0 ℃ of reaction with HCl gas to the intermediate that is obtained by preceding step in ethyl acetate (15ml).d
1FAB-MS: value of calculation: C
27H
33N
5O
4: 491; Measured value: 492 (M+H).
Example C24
Steps A:
EDC is joined by example C23, product (the 5.79g that steps A obtains, 18.1mmol), 2-(methyl mercapto) ethanol (2.49g, 27.1mmol), in the solution that is stirring of DMAP (220mg) in dichloromethane (100ml), then this mixture was stirred 1 day.Reactant mixture is purified on silicagel column then with salt water washing, drying, evaporation, with the hexane solution eluting of 60% ethyl acetate, obtains required compound (6.64g, 94%).FAB-MS: value of calculation: C
20H
30N
2O
4S:394; Measured value: 395 (M+H).
According to example C1, the described program of step C, (6.12g 15.5mmol) 30 minute prepares (5.38g, 95%) in 0 ℃ of reaction with HCl gas to the intermediate that is obtained by preceding step in ethyl acetate (30ml).FAB-MS: value of calculation: C
15H
22N
2O
2S:294; Measured value: 295 (M+H).
According to example C1, the described program of step D, the intermediate that makes by preceding step (2.0g, 5.44mmol), intermediate 1 (2.12g, 5.44mmol), HOBT (1 equivalent), N-methylmorpholine (1 equivalent) and EDC (1.5 equivalent) preparation.Purify by the MPLC method, the hexane solution eluting with the 80-100% ethyl acetate obtains this intermediate (3.44g, 95%).FAB-MS: value of calculation: C
35H
47N
5O
6S:665: measured value: 666 (M+H).
According to example C1, the described program of step C, (2.94g 4.42mmol) 20 minute prepares (2.80g, 99%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (10ml).FAB-MS: value of calculation: C
30H
39N
5O
4S:565: measured value: 566 (M+H).
Other intermediate listed among the table CVII is by the program of establishing previously, and as example C24, the program that steps A and B are exemplified prepares.Final chemical compound is according to example 17 step D and E, with intermediate 1 preparation.
Table CVII
The isomer of intermediate end product sequence number X intermediate end product
MF???????????????????MF
FAB-MS(M+1)?????????FAB-MS(M+1)1????CO
2(CH
2)
2SMe??C
15H
22N
2O
2S????C
30H
39N
5O
4S?????R
295?????????????????5662????CO
2Bn????????????C
19H
22N
2O
2?????C
34H
39N
5O
4??????R
311?????????????????5823????CO
2Bn????????????C
19H
22N
2O
2?????C
34H
39N
5O
4??????S
311?????????????????5824????CO
2(CH
2)
3CH
3?C
16H
24N
2O
2?????C
31H
41N
5O
4??????RS
277?????????????????5485????CO
2(CH
2)
2CH
3?C
15H
22N
2O
2?????C
30H
39N
5O
4??????RS
263?????????????????5346????CO
2CH(CH
3)
2???C
15H
22N
2O
2?????C
30H
39N
5O
4??????RS
263?????????????????5347????CONH(CH
2)
3CH
3?C
16H
25N
3O????????C
31H
42N
6O
3??????RS
276?????????????????5478????CONHCH(CH
3)
2???C
15H
23N
3O????????C
30H
40N
6O
3??????RS
262?????????????????5339????CO
2CH
2CO
2Et???C
16H
22N
2O
4?????C
31H
39N
5O
6??????RS
306?????????????????5781O???CONHEt????????????C
14H
21N
3O????????C
29H
38N
6O
3??????RS
248?????????????????51911???CONHCH
2CO
2Et???C
16H
23N
3O
3??????C
31H
40N
6O
5??????RS
307 577 annotate: preparation RS is to use racemic intermediate during chemical compound, rather than uses chiral intermediate.
Example C24A
(100mg, (120mg, 0.188mmol) in the solution that is stirring in ethanol/water (3/2ml), formed mixture was stirring at room 6 hours 0.467mmol) to join the end product that made by example C24 with sodium metaperiodate.Then this reactant mixture is poured in the saturated sodium bicarbonate solution (10ml), with dichloromethane extraction (10ml, 3 times).Organic extract is merged, after evaporation, get required compound (89mg, 81%).FAB-MS: value of calculation: C
30H
39N
5O
5S:581; Measured value: 582 (M+H).
Example C25
EDC (1.5 equivalent) is joined the intermediate (100mg that is made by example 23, step e, 0.17mmol), 3-(methyl mercapto) propanol (18mg, 0.17mmol) and the solution that stirring of DMAP (3mg) in dichloromethane (15ml) in, with this mixture stirring at room 1 day.This reactant mixture water and salt water washing, drying, evaporation are purified by the MPLC method then, with the hexane solution eluting of 80% ethyl acetate, obtain required compound (88mg).FAB-MS: value of calculation: C
36H
49N
5O
6S:679; Measured value: 680 (M+H).
Step B:
According to example C1, the described program of step C, (85mg 0.125mmol) 20 minute prepares (74mg, 95%) in 0 ℃ of reaction with HCl gas to the intermediate that is obtained by preceding step in ethyl acetate (3ml).FAB-MS: value of calculation: C
31H
41N
5O
4S:579; Measured value: 580 (M+H).
With suitable amine and alcohol, according to the program of establishing above, the program that exemplifies as example C25 has prepared listed chemical compound among the table CVIII.
FAB-MS(M+1)1????CO(morpholine)????C
31H
40N
6O
4
560(M
+,EI?MS)2????CO
2(CH
2)
4SMe??C
32H
43N
5O
4S
5943????CONH(CH
2)
2SMe??C
30H
40N
6O
3S
5654????CONHEt????????????C
29H
38N
6O
3
5195????CONH(CH
2)
2OH???C
29H
38N
6O
4
535
Equally, use by example C23, the intermediate that step C obtains, and according to step D and the described program of E, and use intermediate 3 to replace intermediate 1, the program of having established according to example C25 exemplifies has prepared the chemical compound shown in the table CVIIIa with suitable amine.
Table CVIIIa
Sequence number X MF
FAB-MS(M+1)1??????CONHEt??????????????C
29H
41N
5O
3
5082??????CONH(CH
2)
2OH?????C
29H
41N
5O
4
524
Equally, use by example C23 the intermediate that step e obtains, and press said procedure, or the intermediate that obtains by example C23, steps A, and according to example C24 steps A to the described program of D, with intermediate 1 or intermediate 3, can make listed chemical compound among the table CVIIIb.
Table CVIIIb
Sequence number R1 X1
-CONHCH
32
-CONHCH
33
-CONH (CH
2)
3OH4
-CONH (CH
2)
3OH5
-CONHCH
2CH
2SCH
3
Example C26
Steps A: 3-benzyloxy formamido group pyridine
0 ℃ with benzyl chloroformate (15.2ml, 0.106mol) slowly join the 3-aminopyridine (10g, 0.106mol) and triethylamine (16.3ml is 0.117mol) in the solution in dichloromethane (100ml).This reactant mixture stirring is spent the night, then water, saturated NaHCO
3MgSO is used in washing
4Drying, and evaporate.Residue is purified on silicagel column and is obtained product (9.51g).FAB-MS: value of calculation: C
13H
12N
2O
2: 228 measured values: 229 (M+H).
Step B:3-benzyloxy formylaminopiperidinderivatives
The intermediate that preceding step is made (9.51g, 4.17mmol) and hydrochloric acid (3.5ml, 41.7mmol) the solution PtO in ethanol (300ml)
2(0.9g) and hydrogen (1 atmospheric pressure) carry out hydrogenation reaction and spend the night.Obtain the brown solid product after filtration and the evaporation.FAB-MS: value of calculation: C
13H
18N
2O
2: 234; Measured value: 235 (M+H).
Step C:
In front the intermediate that makes of step (4.65g, 17.2mmol), add EDC (3.94g, 1.2 equivalents) in intermediate 1 (6.68g, equivalent) HOBT (2.32g, 1 equivalent) and the solution of NMM (2.1ml, 1 equivalent) in dichloromethane (100ml).Water, saturated NaHCO during post processing are spent the night in the reactant mixture stirring
3MgSO is used in washing
4Drying, and evaporate.At SiO
2Purify on the post and obtain the required product of 2.5g.FAB-MS: value of calculation: C
33H
43N
5O
8: 605; Measured value: 606 (M+H).
Step D:
Intermediate (2.5g) and Pd (OH) that preceding step is made
2The solution of/C (250mg, 10%) in methanol (60ml) is at H
2Press (1 atmospheric pressure) to stir 3 days down.Reactant mixture obtains desired substance by diatomite filtration after the evaporation.FAB-MS: value of calculation: C
25H
37N
5O
4: 47l; Measured value: 472 (M+H).
0 ℃ of intermediate that makes to preceding step (236mg, 0.5mmol) and N, the N-diisopropyl ethyl amine (0.11ml, 0.6mmol) add in the solution in dichloromethane (10ml) isobutyryl chloride (0.053ml, 0.5mmol).Reactant mixture was stirred 2 hours, and MgSO is used in water, salt water washing then
4Drying, and evaporate.Use SiO
2Post dodges chromatograph purifies, and the hexane solution eluting with the 90-100% ethyl acetate obtains product.FAB-MS: value of calculation: C
29H
43N
5O
5: 541; Measured value: 542 (M+H).
Step F:
At 0 ℃ the HCl bubbling is entered into intermediate that preceding step the makes solution at ethyl acetate (5ml), till saturated.Mixture was stirred 30 minutes, be evaporated to the dried product that obtains.FAB-MS: value of calculation: C
24H
35N
5O
3: 441; Measured value: 442 (M+H).
Similarly, according to foregoing same program, but use different acylating agents to prepare following compounds.
FAB-MS(M+1)1???????????Ac
2O????????????????AcNH??????????C
22H
31N
5O
3
4142????ChxCOCl?????????ChxCONH?????????C
27H
39N
5O
3
4823????ChxCH
2COCl?????ChxCH2CONH??????C
28H
41N
5O
3
4964????BzCl????????????BzNH????????????C
27H
33N
5O
3
4765????PhSO
2Cl????????PhSO2NH?????????C
26H
33N
5O
4S
5126????iso-PrNCO???????iso-PrNHCONH????C
24H
36N
6O
3
457 annotate: Chx: cyclohexyl, Bz: benzoyl
At-78 ℃, (28.3g, THF 0.11mol) (100ml) solution join the KHMDS that is stirring, and (27.4g is in THF 0.138mol) (500ml) solution with the N-t-Boc-3-piperidine ethyl formate in during 20 minutes under argon shield.At-78 ℃ with this solution restir 30 minutes.THF (100ml) solution with 4-bromomethyl thiazole or 4-5-chloromethyl thiazole joins in the reactant mixture at leisure then.4-bromomethyl thiazole be by with the 4-methylthiazol (10ml, 0.11mmol), N-bromosuccinimide (19.6g, 0.11mol) and AIBN (0.2g) at CCl
4Refluxed 2 hours (300ml), cool to room temperature filters, and evaporation prepares then; The 4-5-chloromethyl thiazole can be by Hsiao, people such as C-H; Synthetic Communication, 20 (22), 2507-3417 (1990) and Caldwell, W and Fox, S.M.J.Am.Chem.Soc.73,2935 (1955) described method preparations.The black mixture stirring that generates is spent the night, allow it be warmed to room temperature.With this material concentrate, dilute with water and use ethyl acetate extraction then.The organic layer anhydrous magnesium sulfate drying filters and concentrates.Purify by silica gel column chromatography, the ethyl acetate isohexane mixed liquor eluting with 30-65% solvent gradient obtains title compound (7.58g, 20%).FAB-MS: value of calculation: C
17H
26N
2O
4S:354; Measured value: 355 (M+H).
(7.0g is in ethyl acetate 19.8mmol) (100ml) solution, till saturated at 0 ℃ the hydrogen chloride gas bubbling to be entered into the intermediate that preceding step makes.Under agitation make its reaction 30 minutes, concentrate then and remove ethyl acetate, obtain product (5.3g, 93%).
1H NMR (CDCl
3, 400MHz) δ 9.67 (s, 1H), 7.75 (s, 1H), 4.34-4.15 (2m, 2H), 3.67 (d, J=12.8Hz, 1H), 3.34 (d, J=15Hz, 1H), 3.28 (d, J=12.5Hz, 1H), 3.21 (d, J=15Hz, 1H), 3.01 (dt, J=3.0,12.5Hz, 1H), 2.26 (br.d, J=13.7Hz, 1H), and 1.97-1.92 (m, 1H), 1.80 (dt, J=3.5,13Hz, 1H), and 1.78-1.58 (m, 1H), 1.26 (t, J=7.2Hz, 3H) .FAB-MS: value of calculation: C
12H
18N
2O
2S:254; Measured value: 255 (M+H).
0 ℃ with EDC (7.16g, 37.34mmol) join the intermediate that makes by step B (6g, 18.67mmol), in the solution that is stirring formed of (R)-(-)-(O)-acetyl group mandelic acid (1 equivalent), HOBT (1 equivalent) and NMM (2 equivalent).The reactant mixture stirring is spent the night, allow it be warmed to room temperature during this period.This solution is poured in the saline, uses CH then
2Cl
2Extraction.Organic layer MgSO
4SiO is used in dry, evaporation
2Dodge the color post and purify, the hexane solution eluting with the 40-80% ethyl acetate obtains two kinds of enantiopure compound.The isomer of coming out from chromatographic column earlier is designated as d
1(2.17g, 30%), after the isomer that washes out be designated as d
2(0.87g, 12%), and mix fraction (700mg).The intermediate that these chemical compounds and example C8 steps A is obtained with the NMR method compares and records original spatial chemistry and arrange.The absolute stereo chemistry of these intermediate is then determined by x-ray analysis.This arranging confirmed by the x-ray analysis of intermediate 1 afterwards.FAB-MS: value of calculation: C
22H
26N
2O
5S:430; Measured value: 431 (M+H).d
1:
1H NMR (CDCl
3, 400MHz) show that this chemical compound exists with the form of the mixture of two kinds of conformations.δ 8.77,8.65 (2s, 1H), 7.46-7.34 (m, 5H), 7.07,7.02 (2s, 1H), 6.64,6.23 (2s, 1H), 4.29 (br.d, J=13.9Hz, 1/2H), 4.10-4.02 (m, 3/2H), and 3.92-3.87 (m, 3/2H), 3.61 (d, J=13.5Hz, 1/2H), 3.46 (d, J=14Hz, 1/2H), 3.40-3.32 (m, 1/2H), and 3.25-3.21 (m, 1/2H), 3.18 (d, J=14Hz, 1/2H), 3.06 (d, J=14Hz, 1/2H), 2.96 (d, J=14Hz, 1/2H), 2.84 (d, J=14Hz, 1/2H), 2.85-2.75 (br.m, 1/2H), 2.14,2.11 (2s, 3H), 1.90-1.82 (m, 11/2H), 1.80-1.75 (m, 1H), 1.61-1.55 (m, 1H), 1.50-1.40 (br.m.1/2H), 1.14 (t, J=7Hz, 3/2H), 1.03 (t, J=7Hz, 3/2H) .d
2:
1H NMR (CDCl
3, 400MHz) show that this chemical compound exists with the form of the mixture of two kinds of conformations.δ8.71,8.68(2d,J=1.8Hz,1H),7.41-7.34(m,5H,7.06,6.83(2d,J=1.8Hz,1H),6.41?6.20(2s,1H),4.46(br.d,J=13.4Hz,1/2H),4.24-3.93(m,3H),3.41(d,J=13.5Hz,1/2H),3.31-3.28m,1H),3.13(d,J=14.2Hz,1/2H),3.04(d,J=14.2Hz,1/2H),3.04(d,J=14.2Hz,1/2H),2.92(d,J=14Hz,1/2H),2.73(d,J=14Hz,1/2H),2.54(d,J=13.8Hz,1H),2.30(br.d,J=13Hz),2.15,2.09(2s,3H),2.00-1.95(m,1/2H),1.65-1.49(m,2H),1.37(dt,J=4,12.8Hz,1/2H),1.17-1.10(m,3H).
Step D:
The intermediate d that preceding step is obtained
1(2.0g, 4.65mmol), the solution formed of concentrated hydrochloric acid (25ml) and ethanol (25ml) refluxed 3 hours, was evaporated to dried then.Residue neutralizes with ammonium hydroxide, uses dichloromethane extraction, uses SiO then
2The sudden strain of a muscle chromatographic column was purified, with 1: 10: 90 NH
4OH: MeOH: CHCl
3The mixed solvent eluting, obtain product (0.72g, 61%).
1H NMR (CD
3OD, 400MHz) δ 8.88 (d, J=2Hz, 1H), 7.21 (d, J=2Hz, 1H), 4.20-4.07 (m, 2H), 3.28 (br.d, 1H), 3.06 (d, JAB=14Hz, 1H), 2.97 (d, JBA=14Hz, 1H), 2.92-2.80 (md, 1H), 2.61-2.57 (m, 2H), and 2.21-2.16 (br.d, 1H), 1.66-1.40 (m, 3H), 1.20 (t, J=7.3Hz, 3H) .FAB-MS: value of calculation: C
12H
18N
2O
2S:254; Measured value: 255 (M+H).
0 ℃ with EDC (247mg, 1.28mmol) join the intermediate that makes by preceding step (163mg, 0.642mol), intermediate 1 (250mg, 0.642mmol) and HOBT (87mg is 0.642mmol) in the solution that is stirring in dichloromethane (20ml).The reactant mixture stirring is spent the night, and allow it be warmed to room temperature.This solution washs with saturated sodium-chloride, uses anhydrous magnesium sulfate drying, filters then and evaporates.Purify by the MPLC method,, obtain required compound (285mg, 71%) with the hexane solution eluting of 60% ethyl acetate.FAB-MS: value of calculation: C
32H
43N
5O
6S:625; Measured value: 626 (M+H); 526 (M
+-Boc (100)).
(270mg is in ethyl acetate 0.43mmol) (10ml) solution, till saturated at 0 ℃ the hydrogen chloride gas bubbling to be entered into the intermediate that is made by preceding step.Reaction was under agitation carried out 30 minutes, obtained product (226mg, 93%) after evaporation removes ethyl acetate.
1H NMR (CD3OD, 400MHz): 9.90 (d, J=2.2Hz, 4/5H), 9.5 (d, J=2.2Hz, 1/5H), 8.48 (d, J=7.15,4/5H), 8.15 (d, 7.15,1/5H), 7.70 (d, J=2.2Hz, 4/5H), 7.68 (d, J=2.2,1/5H), 7.55 (d, J=7.89Hz, 1H), 7.27 (d, J=8.0Hz, 1H), 7.06-6.95 (M, 1H), 3.94 (q, J=7.1Hz, 2H), 3.94 (q, J=7.1Hz, 2H), 2.37 (d, J=14.9,1H), 1.90 (d, J=14.9,1H), 1.60 (s, 6H), 1.07 (t, J=7.1Hz, 3H), FAB-MS: value of calculation: C
27H
35N
5O
4S:525; Measured value: 526 (M+H).
Example C27A
According to the program identical with example C27, the product d that obtains with step C
2, made title compound.FAB-MS: value of calculation: C
27H
35N
5O
4S:525 measured value: 526 (M+H).
Use corresponding alkylating reagent, according to top definite, as the program that example C27 steps A and B exemplify, prepared other listed intermediate among the table CX.According to example C1 step D and E, made final chemical compound with intermediate 1.
Midbody product
Midbody product sequence number Y MF MF isomer
255 5263 4-thiazolyl methyl C
12H
18N
2O
2S C
27H
35N
5O
4S RS
255 5264 5-thiazolyl methyl C
12H
18N
2O
2S C
27H
35N
5O
4S RS
255 5265 (4-methyl-2-C
13H
20N
2O
2S C
28H
37N
5O
4S RS
Thiazolyl) methyl 269 5406 (2-methyl-4-C
13H
20N
2O
2S C
28H
37N
5O
4S RS
Thiazolyl) methyl 269 5407 (4-methyl-5-C
13H
20N
2O
2S C
28H
37N
5O
4S RS
Thiazolyl) methyl 269 5408 (5-methyl-4-C
13H
20N
2O
2S C
28H
37N
5O
4S RS
Thiazolyl) methyl 269 540
Example C28
(3: 1,5ml) solution in the mixture stirred 2 days in 60 ℃ at ethanol/water with the end product (50mg) of example C27, NaOH (3N, 5 equivalents).Then reactant mixture is carried out vacuum evaporation and remove ethanol.Residue to pH=1, is evaporated to dried with hcl acidifying then.White residue is purified with silicagel column, the NH with 3/30/70
4OH/MeOH/CHCl
3Eluting obtains required product (25mg).FAB-MS: value of calculation: C
25H
31N
5O
4S:497: measured value: 498 (M+H).
Example C29
Less (the d of polarity that example C27 step C is made
1) (1.5g's intermediate 3.48mmol) refluxed 2 hours in ethanol (10ml) and 5N NaOH (3.5ml).Slowly handle then with the mixture cool to room temperature, and with 3N HCl to pH=11.(1.52g 7mmol), and stirred 2 hours to add Bis(tert-butoxycarbonyl)oxide in the solution that this is stirring.This solution is acidified to pH4, is neutralized to pH7 then, use ethyl acetate extraction 3 times.With organic extract merging, dry, also concentrated, obtain white solid (810mg).
(935mg 4.9mmol) joins in intermediate (800mg), benzyl alcohol (1.27ml) and the solution of DMAP (30mg) in dichloromethane (40ml) that is made by preceding step with EDC.This mixture was at room temperature stirred 3 days, be poured into rare NaHCO then
3In the solution, use ethyl acetate extraction 3 times, use MgSO
4Dry.Purify with dodging chromatographic column in the evaporation back, the hexane solution eluting with the 20-40% ethyl acetate obtains required product (145mg).
Step C:
According to example C1, the described program of step C, intermediate (140mg) that is made by preceding step and HCl gas made 0 ℃ of reaction in ethyl acetate (20ml) in 15 minutes, after the evaporation, residue were dissolved in the dichloromethane solution NH
4The OH washing.Obtain product after organic layer drying, the evaporation.
According to example C1, the described program of step D, the intermediate that makes by preceding step (140mg, 0.443mmol), intermediate 1 (172mg, 0.443mmol), HOBT (60mg) and EDC (170mg) preparation.Purify by the MPLC method,, obtain this intermediate (210mg) with the hexane solution eluting of 80% ethyl acetate.
According to example C1, the described program of step C, (12mg 0.018mmol) prepared in 0 ℃ of reaction in ethyl acetate (3ml) with HCl gas the intermediate that is made by preceding step in 10 minutes.
According to this example by allowing example C29, intermediate that steps A makes and methylamine, ethamine, ethanolamine, 3-aminopropanol or the reaction of 2-(methyl mercapto) ethamine, rather than with step B in benzyl alcohol reaction, and can make with intermediate among the step D 1 or intermediate 3 and to show listed chemical compound among the CXa.
Table CXa
Sequence number R1 X1
-CONHCH
32
-CONHCH
33
-CONHCH
2CH
34
-CONHCH
2CH
35
-CONHCH
2CH
2OH6
-CONHCH
2CH
2OH7
-CONH (CH
2)
3OH8
-CONH (CH
2)
3OH9
-CONH (CH
2)
2SCH
310
-CONH (CH
2)
2SCH
3
Steps A:
According to example C1, the described program of step D, the intermediate that makes by example C27 step D (134mg, 0.528mmol), intermediate 3 (200mg, 0.528mmol), HOBT (71mg, 1 equivalent) and EDC (200mg, 2 equivalents) preparation.Purify by the MPLC method,, obtain this intermediate (160mg, 49%) with the hexane solution eluting of 60% ethyl acetate.FAB-MS: value of calculation: C
32H
46N
4O
6S:606: measured value: 607 (M+H).
According to example C1, the described program of step C, (155mg 0.252mmol) 10 minute prepares (142mg, 96%) in 0 ℃ of reaction with HCl gas to the intermediate that is made by preceding step in ethyl acetate (5ml).FAB-MS: value of calculation: C
27H
38N
4O
4S:506: measured value: 507 (M+H).
(0.89g, (2.00g is 6.26mmol) and in the solution that is stirring of DMF (3) in benzene (20ml) 6.89mmol) slowly to join the product that example 15 steps make with oxalyl chloride at 0 ℃.Reaction was under agitation carried out 10 minutes at 0 ℃, at room temperature carried out 20 minutes again.To obtain acyl chlorides after the reactant mixture vacuum evaporation, need not further to purify and to use it in next step reaction.(the gained mixture was stirring at room 30 minutes for 1.22g, water 18.8mmol) (3ml) solution to add Hydrazoic acid,sodium salt in the solution of the above-mentioned residue that is stirring in 5 ℃ of acetone (20ml).The reactant mixture evaporation is removed acetone, and dilute with water is used extracted with diethyl ether then.The ether extract is merged, use MgSO
4Dry.Obtain thick azide after filtration and the evaporation, need not further purification can use.The gained material is dissolved in the toluene (70ml), and refluxing spends the night obtains the isocyanates toluene solution.FAB-MS: value of calculation: C
18H
24N
2O
3: 316; Measured value: 217 (M+H-BOC (100)).
Step B:
The solution that top step is made (get 15ml among the 70ml, 1.3mmol) and the solution formed of methanol (5ml) reflux and spend the night.With the reactant mixture evaporation, obtain white solid (331mg).FAB-MS: value of calculation: C
19H
28N
2O
4: 348: measured value: 349 (M+H).
Step C:
Chlorine hydrogen bubbling is proceeded in the solution of intermediate (271mg) in 0 ℃ of ethyl acetate (15ml) that preceding step makes, until bubble and till.The reaction under agitation carried out 30 minutes, up to the TLC analysis result show react completely till.This solution concentration is removed ethyl acetate, obtain product (284mg).FAB-MS: value of calculation: C
14H
20N
2O
2: 248; Measured value: 249 (M+H).
According to example C1, the described program of step D, by the intermediate of preceding step preparation (0.284g, 1mmol), intermediate 1 (0.388g, 1mmol), HOBT (1 equivalent), N-methylmorpholine (1 equivalent) and EDC (1.5 equivalent) prepare.Purify by the MPLC method,, obtain intermediate (0.35g) with the hexane solution eluting of 60% ethyl acetate.FAB-MS: value of calculation: C
34H
45N
5O
6: 619; Measured value: 620 (M+H).
Step e:
The hydrogen chloride gas bubbling is entered into the intermediate that preceding step makes, and (200mg is mmol) in the solution in 0 ℃ of ethyl acetate (10ml), till saturated.Reaction was under agitation carried out 30 minutes.Concentrate then and remove ethyl acetate, obtain product (158mg).FAB-MS: value of calculation: C
29H
37N
5O
4: 519: measured value: 520 (M+H).
With EDC (1.55g, 1.5 equivalent) break into portions joins example C2, step C (HCl salt, 2.51g, 5.34mmol), N-Boc-beta-amino-Beta-methyl-butanoic acid (1.16g, 1 equivalent), in NMM (0.6ml, 1 equivalent) and the suspension of DMAP (33mg, 0.05 equivalent) in dichloromethane (30ml).Reactant mixture becomes limpid very soon, and it was stirred 3 hours, with the dichloromethane dilution, with 3N HCl, saline and saturated sodium bicarbonate solution washing, carries out post processing.Organic layer MgSO
4Dry, evaporation are purified by silica gel column chromatography then, with the hexane solution eluting of 60% ethyl acetate, obtain required compound (3.40g, 100%).FAB-MS: value of calculation: C
36H
48N
4O
6: 632; Measured value: 633 (M+H).
Step B:
HCl gas bubbling is entered into the intermediate that preceding step makes, and (3.28g is 5.18mmol) in the solution in 0 ℃ of ethyl acetate (30ml).Under agitation reacted 10 minutes, and be evaporated to dried then.Residue is dissolved in the dichloromethane, to wherein adding ether.Filter and collect formed solids, it is carried out vacuum drying, be allowed to condition under the fine vacuum and spend the night, obtain product (2.44g, 83%).FAB-MS: value of calculation: C
31H
40N
4O
4: 532; Measured value: 533 (M+H).
Similarly, according to above-mentioned identical program, but the aminoacid (making its deprotection by top described method subsequently) that is to use different Boc to protect has prepared following compounds.
FAB-MS(M+1)1??????????D-Ala-??????????????????C
29H
36N
4O
4
5052??????????L-Ala-??????????????????C
29H
36N
4O
4
5053??????????β-Ala-?????????????????C
29H
36N
4O
4
5054??????????DL-α-Me-Ser-???????????C
30H
38N
4O
5
5318??????????N-Me-Aib-???????????????C
31H
40N
4O
4
533
With sodium cyanoborohydride (134mg, 1.5 equivalent) slowly join the product (808mg that example C32 makes, 1.42mmol), (R)-glyceraldehyde acetone solvate (923mg, 5 equivalents) and sodium acetate (582mg, 5 equivalents) in the solution that is stirring in 0 ℃ of methanol (15ml), the gained mixture is in stirred overnight at room temperature.Mixture evaporation is removed methanol, and make it between sodium bicarbonate solution and dichloromethane are biphase, distribute.Isolate organic layer, water layer uses dichloromethane extraction more than twice.The organic extract dried over mgso that merges, and by the silicagel column purification, the dichloromethane solution eluting with 5-10% methanol obtains product (835mg, 91%).FAB-MS: value of calculation: C
37H
50N
4O
6: 646: measured value: 647 (M+H).
Example C34
(367mg, (3N 1ml), at room temperature stirred the gained mixture 1 day the product that makes to example C33 to add hydrochloric acid in methanol 0.566mmol) (10ml) solution.Reactant mixture is carried out vacuum evaporation, add toluene, carry out vacuum evaporation again,, obtain product (350mg, 99%) to remove moisture.FAB-MS: value of calculation: C
34H
45N
4O
5: 606; Measured value: 607 (M+H).
According to example C1 steps A and the described program of B, in alkylation step, prepared the intermediate of other replacements and shown listed product among the CXII with the benzyl halide that suitably replaces.Change functional group in stage as required at intermediate preparation step B,, nitro is changed into amine and acetamide, and ester is changed into acid (step D) so that by the described standard method of document cyano group is changed into phosphoamide, ester and tetrazolium as required.
Table X II: additional example
Midbody product
Midbody product sequence number R
12MF MF isomer
FAB-MS (M+1) FAB-MS (M+1) 1 o-cyano group C
16H
20N
2O
2C
31H
37N
5O
4D1
273 544 d22 m-cyano group C
16H
20N
2O
2C
31H
37N
5O
4D1
273 544 d23 p-cyano group C
16H
20N
2O
2C
31H
37N
5O
4D1
273????????????????544????????????????d24????p-NH2OC-??????????C
16H
22N
2O
3????C
31H
37N
5O
4?????RS
291????????????????5625????p-EtO2C-??????????C
18H
25NO
4??????C
33H
42N
4O
6?????d1
320????????????????591????????????????d26????p-HO
2C-????????????????????????????C
31H
38N
4O
6?????d1
563 d27 p-(1H-tetrazolium-5-yl) C
16H
21N
5O
2C
31H
38N
8O
4RS
316????????????????5878????m-NH
2OC-?????????C
16H
22N
2O
3????C
31H
37N
5O
4?????RS
291????????????????5629????m-EtO
2C-?????????C
18H
25NO
4??????C
33H
42N
4O
6?????d1
320????????????????591????????????????d210???m-HO
2C-?????????????????????????????C
31H
38N
4O
6????d1
563 d211 m-(1H-tetrazolium-5-yl) C
16H
21N
5O
2C
31H
38N
8O
4RS
316???????????????58712??o-NH
2OC-????????C
16H
22N
2O
3???C
31H
37N
5O
4????RS
291???????????????56213??o-EtO
2C-????????C
18H
25NO
4?????C
33H
42N
4O
6?????d1
320???????????????591????????????????d214??o-HO
2C-??????????????????????????C
31H
38N
4O
6?????d1
563 d215 o-(1H-tetrazolium-5-yl) C
16H
21N
5O
2C
31H
38N
8O
4RS
316???????????????58716??p-AcNH-??????????C
17H
24N
2O
3???C
32H
41N
5O
5?????RS
305????????????????57617??m-AcNH-??????????C
17H
24N
2O
3???C
32H
41N
5O
5?????RS
305???????????????576
Though the present invention is described with reference to its some specific embodiments and is illustrated, but those personnel that are familiar with this gate technique will know, need not to deviate from the spirit and scope of the present invention, just can make various modifications, change, improvement, substitute, delete or increase program and experimental program.For example, other effective dose except that above-mentioned given dose also may be suitable for, and this is the mammal discrepant result in response who any symptom is treated owing to The compounds of this invention already pointed out.Equally, the response of science of viewed particular drug also may according to and because of selected concrete reactive compound or do not have pharmaceutical carrier to exist and the formulation types and the administering mode that are adopted different, the more such expections on the result change or difference purpose also according to the invention and practices.Therefore, intention is that the present invention is determined by claim scope subsequently.And like this some claim so long as reasonably will broadly be explained.
Claims (30)
1. the chemical compound of general formula I and pharmaceutically acceptable salt thereof and each diastereomer:
Formula I is wherein:
R
1Be selected from C
1-C
10Alkyl, aryl, aryl (C
1-C
6Alkyl), (C
3-C
7Cycloalkyl) (C
1-C
6Alkyl)-, (C
1-C
5Alkyl)-K-(C
1-C
5Alkyl)-, aryl (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-and (C
3-C
7Cycloalkyl) (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-, wherein K is O, S (O) m, N (R
2) C (O), C (O) N (R
2), OC (O), C (O) O ,-CR
2=CR
2-or-C ≡ C-, wherein aryl is selected from: phenyl, naphthyl, azaindole, pyridine radicals, benzothienyl, benzofuranyl, thiazolyl and benzimidazolyl, R
2With alkyl can be further by 1-9 halogen ,-S (O) mR
2a, a 1-3 OR
2aOr C (O) OR
2aReplace, aryl can be further by 1-3 C
1-C
6Alkyl, a 1-3 halogen, a 1-2 OR
2, the dioxy methylene ,-S (O) mR
2, 1-2-CF
3,-OCF
3, nitro ,-N (R
2) C (O) (R
2) ,-C (O) OR
2,-C (O) N (R
2) (R
2) ,-1H-tetrazolium-5-base ,-SO
2N (R
2) (R
2) ,-N (R
2) SO
2Phenyl or-N (R
2) SO
2R
2Replace;
R
2Be selected from: hydrogen, C
1-C
6Alkyl and C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly be connected to form a C
3-C
8Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
2aBe hydrogen, or the C that is randomly replaced by alkyl
1-C
6Alkyl;
R
3Be selected from: hydrogen ,-(CH2)
rPhenyl ,-(CH2)
rNaphthyl ,-C1-C
10Alkyl ,-C3-C
7Cycloalkyl, wherein phenyl, naphthyl and C3-C
7Cycloalkyl ring can be selected from following substituting group by 1-3 and replace: C1-C
6Alkyl, halogen ,-OR2、-NHSO
2CF
3、
-(CH
2)
rOR
6, -(CH
2)
rN(R
2)(R
6),-(CH
2)
r(R
6),-(CH
2)
rC(O)OR
2,
-(CH
2)
rC(O)OR
6,-(CH
2)
rOC(O)R
2,-(CH
2)
rOC(O)R
6,
-(CH2)
rC(O)R
2,-(CH2)
rC(O)R
6,-(CH
2)
rC(O)N(R
2)(R
2),
-(CH
2)
rC(O)N(R
2)(R
6),-(CH
2)
rN(R
2)C(O)R
2-(CH
2)
rN(R
2)C(O)R
6,
-(CH2)
rN(R6)C(O)R2,-(CH2)
rN(R
6)C(O)R
6,-(CH
2)
rN(R
2)C(O)OR
2,
-(CH
2)
rN(R
2)C(O)OR
6,-(CH
2)
rN(R
6)C(O)OR
2,
-(CH
2)
rN(R
6)C(O)OR
6,-(CH
2)
rN(R
2)C(O)N(R
2)(R
6),
-(CH
2)
rN(R
2)C(O)N(R
2)(R
2),-(CH
2)
rN(R
6)C(O)N(R
2)(R
6),
(CH
2)
rN(R
2)SO
2R
6,-(CH
2)
rN(R
2)SO
2R
2,-(CH
2)
rN(R
6)SO
2R
2,
CH
2)
rN(R
6)SO
2R
6,-(CH
2)
rOC(O)N(R
2)(R
6),
-(CH
2)
rOC(O)N(R
2)(R
2),-(CH
2)
rSO
2N(R
2)(R
6),
-(CH
2)
rSO
2N(R
2)(R
2),(CH
2)
rSO
2NHC(O)R
6,-(CH
2)
rSO
2NHC(O)R
2,
-(CH
2)
rSO
2NHC(O)OR
6,-(CH
2)
rSO
2NHC(O)OR
2,
-(CH
2)
rC(O)NHC(O)NR
2,-(CH
2)
rC(O)NHC(O)NR
6,
-(CH
2)
rC(O)NHC(O)R
2,-(CH
2)
rCONHC(O)R
6,
-(CH
2)
rCONHSO
2R
6,-(CH
2)
rCONHSO
2R
2,
-(CH
2)
rCONHSO
2N(R
2)R
2),-(CH
2)
rCONHSO
2N(R
2)R
6),
-(CH
2)
rN(R
2)SO
2N(R
2)R
6),-(CH
2)
rN(R
6)SO
2N(R
2)R
6),
-(CH
2)
rS(O)
mR
6, and-(CH2)
rS(O)
mR
2;
R
3aBe hydrogen or the C that randomly replaced by hydroxyl
1-C
6Alkyl;
W is selected from: hydrogen ,-CN ,-C (O) OR
8,-C (O) OR
2,-C (O) O (CH
2)
lAryl ,-C (O) N (R
2) (R
2);-C (O) N (R
2) (R
8) ,-C (O) N (R
2) (CH
2)
lAryl ,-CH
2N (R
2) C (O) R
8-CH
2N (R
2) C (O) (CH
2)
lAryl ,-(CH
2)
rOR
2,-CH (OH) R
2,-CH (OH) (CH
2) aryl ,-C (O) R
2,-C (O) (CH
2) aryl, 1H-tetrazolium-5-base, 5-amino-1,2,4-4-oxadiazole-3-base and 5-methyl isophthalic acid, 2,4-4-oxadiazole-3-base, wherein R
8Be hydrogen, C
1-C
6Alkyl or by OR
2, C (O) OR
2, CON (R
2) (R
2), N (R
2) C (O) R
2, N (R
2) C (O) N (R
2) (R
2) C that replaces
1-C
6Alkyl, and aryl is phenyl, pyridine radicals or 1H-tetrazolium-5-base;
X is selected from: hydrogen ,-C ≡ N ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl ,-(CH
2)
qOR
2,-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl ,-(CH
2)
qOC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qOC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) R
2,-(CH
2)
qC (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qN (R
2) SO
2N (R
2) (R
2) ,-(CH
2)
qS (O)
mR
2And-(CH
2)
qS (O)
m(CH
2)
tAryl, wherein R
2, (CH
2)
q(CH
2)
tGroup can be randomly by 1-2 C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl, CONH
2, S (O)
mCH
3, carboxylic acid C
1-C
4Arrcostab or 1H-tetrazolium-5-base replaces, and aryl is phenyl, naphthyl, pyridine radicals, thiazolyl or 1H-tetrazolium-5-base group, these groups can be randomly by 1-3 halogen, 1-3 individual-OR
2,-CON (R
2) (R
2) ,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O)
mR
2Or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
10Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
3-C
7Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAlkyl ,-(CH
2)
q-K-(CH
2)
t(contain O, NR
2, S C
3-C
7Cycloalkyl) and-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl), wherein K is O, S (O) m, C (O) NR
2, CH=CH, C ≡ C, N (R
2) C (O), C (O) NR
2, C (O) O or OC (O), and wherein alkyl, R
2, (CH
2)
q(CH
2)
tGroup can be randomly by C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl ,-CONH
2Or the C of carboxylic acid
1-C
4Arrcostab replaces, and aryl is phenyl, naphthyl, pyridine radicals, 1-H-tetrazolium-5-base, thiazolyl, imidazole radicals, indyl, pyrimidine radicals, thiadiazolyl group, pyrazolyl, oxazolyl, isoxazolyl, thienyl, quinolyl, pyrazinyl or isothiazolyl, these groups can be randomly by 1-3 halogen, 1-3-OR
2,-C (O) OR
2,-C (O) N (R
2) (R
2), nitro, cyano group, benzyl, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2Or 1H-tetrazolium-5-base replaces; Its condition is R
3, have at least one not to be hydrogen among W, X and the Y;
R
4And R
5Be hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6Alkyl, wherein substituent group can be 1-5 halogen, a 1-3 hydroxyl, a 1-3 C
1-C
10Alkanoyloxy, a 1-3 C
1-C
6Alkoxyl, phenyl, phenoxy group, 2-furyl, C
1-C
6Alkoxy carbonyl group, S (O) m (C
1-C
6Alkyl); Perhaps R
4And R
5Can lump together formation-(CH
2)
dL
a(CH
2)
e-, L wherein
aBe C (R
2)
2, O, S (O) m or N (R
2), d and e are 1-3 independently, R
2Definition the same;
Z is N-R
6aOr O, wherein R
6aBe hydrogen or C
1-C
6Alkyl;
R
6Be hydrogen, C
1-C
6Alkyl or (CH
2)
vAryl, wherein said alkyl and (CH
2)
vGroup can be randomly by 1-2 O (R
2), S (O) mR
2, 1H-tetrazolium-5-base, C (O) OR
2, C (O) N (R
2) (R
2) or SO
2N (R
2) (R
2), N (R
2) C (O) N (R
2) (R
2) replace, and wherein aryl is phenyl, pyridine radicals, 1H-tetrazolium-5-base, triazolyl, imidazole radicals, thiazolyl, pyrazolyl, thiadiazolyl group, imidazolone-1-base, benzimidazolyl-2 radicals-Ji, triazoline ketone group, randomly by C
1-C
6Alkyl, C
3-C
6Cycloalkyl, amino or hydroxyl replace;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, trifluoromethyl, phenyl, replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, C (O) O (C
1-C
6Alkyl), C
3-C
7Cycloalkyl, N (R
2) (R
2), C (O) N (R
2) (R
2); Perhaps R
7And R
7aCan be independently and R
4And R
5One of in the group or both connect, at end nitrogen-atoms and R
7Or R
7aForm alkylidene bridge between the moieties of group, wherein said bridge contains 1-5 carbon atom; Perhaps R
7And R
7aCan be connected to form a C each other
3-C
7Cycloalkyl;
L is 0,1 or 2;
M is 0,1 or 2;
N is 1,2 or 3;
Q is 0,1,2,3 or 4;
R is 0,1,2 or 3;
T is 0,1,2 or 3;
V is 0,1 or 2.
2. the chemical compound of general formula AI and pharmaceutically acceptable salt thereof and each diastereomer:
Formula AI is wherein:
R
1Be selected from C
1-C
10Alkyl, aryl, aryl (C
1-C
6Alkyl), (C
3-C
7Cycloalkyl) (C
1-C
6Alkyl)-, (C
1-C
5Alkyl)-K-(C
1-C
5Alkyl)-, aryl (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-and (C
3-C
7Cycloalkyl) (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-, wherein K is O, S (O) m, N (R
2) C (O), C (O) N (R
2), OC (O), C (O) O ,-CR
2=CR
2-or-C ≡ C-, wherein aryl is selected from: phenyl, naphthyl, azaindole, pyridine radicals, benzothienyl, benzofuranyl, thiazolyl and benzimidazolyl, R
2With alkyl can be further by 1-9 halogen ,-S (O) mR
2a, a 1-3 OR
2aOr C (O) OR
2aReplace, aryl can be further by 1-3 C
1-C
6Alkyl, a 1-3 halogen, a 1-2 OR
2, the dioxy methylene ,-S (O) mR
2, 1-2-CF
3,-OCF
3, nitro ,-N (R
2) C (O) (R
2) ,-C (O) OR
2,-C (O) N (R
2) (R
2) ,-1H-tetrazolium-5-base ,-SO
2N (R
2) (R
2) ,-N (R
2) SO
2Phenyl or-N (R
2) SO
2R
2Replace;
R
2Be selected from: hydrogen, C
1-C
6Alkyl and C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly be connected to form a C
3-C
8Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
2aBe hydrogen, or the C that is randomly replaced by alkyl
1-C
6Alkyl;
R
3Be selected from: hydrogen ,-(CH2)
rPhenyl ,-(CH2)
rNaphthyl ,-C1-C
10Alkyl ,-C3-C
7Cycloalkyl, wherein phenyl, naphthyl and C3-C
7Cycloalkyl ring can be selected from following substituting group by 1-3 and replace: C1-C
6Alkyl, halogen ,-OR2、-NHSO
2CF
3、
-(CH
2)
rOR
6,-(CH
2)
rN(R
2)(R
6),-(CH
2)
r(R
6),-(CH
2)
rC(O)OR
2,
-(CH
2)
rC(O)OR
6,-(CH2)rOC(O)R2,-(CH2)rOC(O)R6,
-(CH2)
rC(O)R
2,-(CH2)
rC(O)R
6,-(CH
2)
rC(O)N(R
2)(R
2),
-(CH
2)
rC(O)N(R
2)(R
6),-(CH
2)
rN(R
2)C(O)R
2 -(CH
2)
rN(R
2)C(O)R
6,
-(CH2)
rN(R
6)C(O)R
2,-(CH
2)
rN(R
6)C(O)R
6,-(CH
2)
rN(R
2)C(O)OR
2,
-(CH
2)
rN(R
2)C(O)OR
6,-(CH
2)
rN(R
6)C(O)OR
2,
-(CH
2)
rN(R
6)C(O)OR
6,-(CH
2)
rN(R
2)C(O)N(R
2)(R
6),
-(CH
2)
rN(R
2)C(O)N(R
2)(R
2),-(CH
2)
rN(R
6)C(O)N(R
2)(R
6),
-(CH
2)
rN(R
2)SO
2R
6,-(CH
2)
rN(R
2)SO
2R
2,-(CH
2)
rN(R
6)SO
2R
2,
-(CH
2)
rN(R
6)SO
2R
6,-(CH
2)
rOC(O)N(R
2)(R
6),
-(CH
2)
rOC(O)N(R
2)(R
2),-(CH
2)
rSO
2N(R
2)(R
6),
-(CH
2)
rSO
2N(R
2)(R
2),(CH
2)
rSO
2NHC(O)R
6,-(CH
2)
rSO
2NHC(O)R
2,
-(CH
2)
rSO
2NHC(O)OR
6,-(CH
2)
rSO
2NHC(O)OR
2,
-(CH
2)
rC(O)NHC(O)NR
2,-(CH
2)
rC(O)NHC(O)NR
6,
-(CH
2)
rC(O)NHC(O)R
2,-(CH
2)
rCONHC(O)R
6,
-(CH
2)
rCONHSO
2R
6,-(CH
2)
rCONHSO
2R
2,
-(CH
2)
rCONHSO
2N(R
2)(R
2),-(CH
2)
rCONHSO
2N(R
2)(R
6),
-(CH
2)
rN(R
2)SO
2N(R
2)R
6),-(CH
2)
rN(R
6)SO
2N((R
2)(R
6),
-(CH
2)
rS(O)
mR
6, and-(CH2)
rS(O)
mR
2;
R
3aBe hydrogen or the C that randomly replaced by hydroxyl
1-C
6Alkyl;
W is selected from :-CN ,-C (O) OR
8,-C (O) OR
2,-C (O) O (CH
2)
lAryl ,-C (O) N (R
2) (R
2);-C (O) N (R
2) (R
8) ,-C (O) N (R
2) (CH
2)
lAryl ,-CH
2N (R
2) C (O) R
8-CH
2N (R
2) C (O) (CH
2)
lAryl ,-(CH
2)
rOR
2,-CH (OH) R
2,-CH (OH) (CH
2) aryl ,-C (O) R
2,-C (O) (CH
2) aryl, 1H-tetrazolium-5-base, 5-amino-1,2,4-4-oxadiazole-3-base and 5-methyl isophthalic acid, 2,4-4-oxadiazole-3-base, wherein R
8Be hydrogen, C
1-C
6Alkyl or by OR
2, C (O) OR
2, CON (R
2) (R
2), N (R
2) C (O) R
2, N (R
2) C (O) N (R
2) (R
2) C that replaces
1-C
6Alkyl, and aryl is phenyl, pyridine radicals or 1H-tetrazolium-5-base;
X is selected from: hydrogen ,-C ≡ N ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl-(CH
2)
qOR
2,-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl-(CH
2)
qOC (O) N (R
2) (CH
2)
tAryl-(CH
2)
qOC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) R
2,-(CH
2)
qC (O) (CH
2)
tAryl-(CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qN (R
2) SO
2N (R
2) (R
2) ,-(CH
2)
qS (O)
mR
2And-(CH
2)
qS (O)
m(CH
2)
tAryl is R wherein
2, (CH
2)
q(CH
2)
tGroup can be randomly by 1-2 C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab or 1H-tetrazolium-5-base replaces, and aryl is phenyl, naphthyl, pyridine radicals, thiazolyl or 1H-tetrazolium-5-base group, these groups can be randomly by 1-3 halogen, 1-3 individual-OR
2,-CON (R
2) (R
2) ,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2Or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
10Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
3-C
7Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl ,-(CH
2)
q-K-(CH
2)
t(contain O, NR
2, S C
3-C
7Cycloalkyl) and-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl), wherein K is O, S (O) m, C (O) NR
2, CH=CH, C ≡ C, N (R
2) C (O), C (O) NR
2, C (O) O or OC (O), and wherein alkyl, R
2, (CH
2)
q(CH
2)
tGroup can be randomly by C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl ,-CONH
2Or the C of carboxylic acid
1-C
4Arrcostab replaces, and aryl is phenyl, naphthyl, pyridine radicals, 1-H-tetrazolium-5-base, thiazolyl, imidazole radicals, indyl, pyrimidine radicals, thiadiazolyl group, pyrazolyl, oxazolyl, isoxazolyl, thienyl, quinolyl, pyrazinyl or isothiazolyl, these groups can be randomly by 1-3 halogen, 1-3-OR
2,-C (O) OR
2,-C (O) N (R
2) (R
2), nitro, cyano group, benzyl, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2Or 1H-tetrazolium-5-base replaces;
R
4And R
5Be hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6Alkyl, wherein substituent group can be 1-5 halogen, a 1-3 hydroxyl, a 1-3 C
1-C
10Alkanoyloxy, a 1-3 C
1-C
6Alkoxyl, phenyl, phenoxy group, 2-furyl, C
1-C
6Alkoxy carbonyl group, S (O) m (C
1-C
6Alkyl); Perhaps R
4And R
5Can lump together formation-(CH
2)
dL
a(CH
2)
e-, L wherein
aBe C (R
2)
2, O, S (O) m or N (R
2), d and e are 1-3 independently, R
2Definition the same;
Z is N-R
6aOr O, wherein R
6aBe hydrogen or C
1-C
6Alkyl;
R
6Be hydrogen, C
1-C
6Alkyl or (CH
2)
vAryl, wherein said alkyl and (CH
2)
vGroup can be randomly by 1-2 O (R
2), S (O) mR
2, 1H-tetrazolium-5-base, C (O) OR
2, C (O) N (R
2) (R
2) or SO
2N (R
2) (R
2), N (R
2) C (O) N (R
2) (R
2) replace, and wherein aryl is phenyl, pyridine radicals, 1H-tetrazolium-5-base, triazolyl, imidazole radicals, thiazolyl, pyrazolyl, thiadiazolyl group, imidazolone-1-base, benzimidazolyl-2 radicals-Ji, triazoline ketone group, randomly by C
1-C
6Alkyl, C
3-C
6Cycloalkyl, amino or hydroxyl replace;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, trifluoromethyl, phenyl, replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, C (O) O (C
1-C
6Alkyl), C
3-C
7Cycloalkyl, N (R
2) (R
2), C (O) N (R
2) (R
2); Perhaps R
7And R
7aCan be independently and R
4And R
5One of in the group or both connect, at end nitrogen-atoms and R
7Or R
7aForm alkylidene bridge between the moieties of group, wherein said bridge contains 1-5 carbon atom; Perhaps R
7And R
7aCan be connected to form a C each other
3-C
7Cycloalkyl;
L is 0,1 or 2;
M is 0,1 or 2;
N is 1,2 or 3;
Q is 0,1,2,3 or 4;
R is 0,1,2 or 3;
T is 0,1,2 or 3;
V is 0,1 or 2.
3. the chemical compound of claim 2 and pharmaceutically acceptable salt thereof and each diastereomer: wherein:
R
1Be selected from: C
1-C
10Alkyl, aryl (C
1-C
4Alkyl)-, C
3-C
6Cycloalkyl (C
1-C
4Alkyl)-, (C
1-C
4Alkyl)-K-(C
1-C
2Alkyl)-, aryl (C
0-C
2Alkyl)-K-(C
1-C
2Alkyl)-and (C
3-C
7Cycloalkyl) (C
0-C
2Alkyl)-K-(C
1-C
2Alkyl)-, wherein K is O, S (O) m, OC (O), C (O) O, and alkyl group can be further by 1-7 halogen, S (O) mR
2, a 1-3 OR
2Or C (O) OR
2Replace, aryl is phenyl, naphthyl, indyl, pyridine radicals, benzothienyl or benzofuranyl, and these groups can be further by 1-2 C
1-C
4Alkyl, a 1-2 halogen, a 1-2 OR
2, S (O) mR
2Or C (O) OR
2Replace;
R
2Be hydrogen, C
1-C
6Alkyl or C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
4-C
7Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
3Be hydrogen or phenyl, phenyl can be randomly at the ortho position by C
1-C
6Alkyl group ,-NHSO
2CF
3,-(CH
2)
r(1H-tetrazolium-5-yl) ,-(CH
2)
rC (O) OR
2, (CH
2)
rC (O) N (R
2) (R
6) replace;
R
3aBe hydrogen, or C
1-C
4Alkyl;
W is-CN ,-C (O) OR
2,-C (O) N (R
2) (R
2) ,-C (O) N (R
2) (CH
2)
lPhenyl, 1H-tetrazolium-5-base, or-(CH
2)
rOR
2
X be hydrogen ,-(CH
2)
qC (O) N (R
2) (R
6), or-CH
2)
qC (O) OR
2
Y is hydrogen, C
1-C
8Alkyl ,-(CH
2)
tPhenyl ,-(CH
2)
tPyridine radicals or-(CH
2)
tThiazolyl;
R
4And R
5Be hydrogen, C independently
1-C
6Alkyl or the C that replaces
1-C
6Alkyl, wherein substituent group can be 1-5 halogen, a 1-3 hydroxyl, S (O)
m(C
1-C
6Alkyl) or phenyl;
R
6Be hydrogen, or C
1-C
6Alkyl;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, trifluoromethyl, phenyl, replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, C (O) O (C
1-C
6Alkyl), C
5-C
7Cycloalkyl, N (R
2) (R
2), C (O) N (R
2) (R
2); Perhaps R
7And R
7aCan be connected to R independently
4Or R
5In one of on, at end nitrogen-atoms and R
7Or R
7aForm alkylidene bridge between the moieties of group, become 5 or 6 yuan of rings; Perhaps R
7And R
7aCan C of interconnection formation
3Cycloalkyl;
L is 0 or 1;
N is 2;
M is 0,1 or 2;
R is 0,1,2 or 3;
Q is 0 or 1;
T is 0 or 1.
4. the chemical compound of the claim 2 shown in the general formula AIb and pharmaceutically acceptable salt thereof and each diastereomer:
Formula AIb is wherein:
R
1Be selected from C
1-C
10Alkyl, aryl (C
1-C
3Alkyl)-and aryl (C
0-C
1Alkyl)-K-(C
1-C
2Alkyl)-, wherein K is O or S (O) m, and aryl is phenyl, pyridine radicals, naphthyl or indyl, and these groups can be randomly by 1-2 C
1-C
4Alkyl, a 1-2 halogen, a 1-2 OR
2, S (O) mR
2Or C (O) OR
2Replace;
R
2Be hydrogen, C
1-C
6Alkyl or C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
5-C
7Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
3Be hydrogen or randomly can be by C at the ortho position
1-C
3Alkyl group, (CH
2)
r(1H-tetrazolium-5-yl) or (CH
2)
rC (O) OR
2The phenyl that replaces;
R
3aBe hydrogen or C
1-C
4Alkyl;
W is-CN ,-C (O) OR
2, or-C (O) N (R
2) (R
2);
X is hydrogen or C (O) OR
2
Y is that hydrogen, benzyl, skin are examined acyl group (picoyl) or thiazolyl methyl;
R
4And R
5Be hydrogen, C independently
1-C
3The C of alkyl, replacement
1-C
3Alkyl, wherein substituent group can be a 1-2 hydroxyl;
R
7And R
7aBe hydrogen or C independently
1-C
4Alkyl;
M is 0,1 or 2;
R is 0,1 or 2.
7. the chemical compound of Formula B I and pharmaceutically acceptable salt thereof and each diastereomer:
Formula BI is wherein:
R
1Be selected from following groups: C
1-C
10Alkyl, aryl, aryl (C
1-C
6Alkyl), (C
3-C
7Cycloalkyl) (C
1-C
6Alkyl)-, (C
1-C
5Alkyl)-K-(C
1-C
5Alkyl)-, aryl (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-and (C
3-C
7Cycloalkyl) (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-, wherein K is O, S (O) m, N (R
2) C (O), C (O) N (R
2), OC (O), C (O) O ,-CR
2=CR
2-, or-C ≡ C-, wherein aryl is selected from: phenyl, naphthyl, indyl, azaindolyl, pyridine radicals, benzothienyl, benzofuranyl, thiazolyl and benzimidazolyl, and R
2With alkyl can be further by 1-9 halogen, S (O) mR
2a, a 1-3 OR
2aOr C (O) OR
2aReplace, aryl can be further by 1-3 C
1-C
6Alkyl, a 1-3 halogen, a 1-2 OR
2, methylene-dioxy ,-S (O) mR
2, 1-2-CF
3,-OCF
3, nitro ,-N (R
2) C (O) (R
2) ,-C (O) OR
2,-C (O) N (R
2) (R
2) ,-1H-tetrazolium-5-base ,-SO
2N (R
2) (R
2) ,-N (R
2) SO
2Phenyl, or-N (R
2) SO
2R
2Replace;
R
2Be selected from: hydrogen, C
1-C
6Alkyl and C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
3-C
8Cyclic ring randomly contains aerobic, sulfur or NR
3a, R wherein
3aBe hydrogen or C
1-C
6Alkyl randomly can be replaced by hydroxyl;
R
2aBe hydrogen or the C that randomly replaced by hydroxyl
1-C
6Alkyl;
R
3Be selected from :-(CH2)
rPhenyl ,-(CH2)
rNaphthyl ,-C1-C
10Alkyl ,-C3-C
7Cycloalkyl, and phenyl, naphthyl and C3-C
7The ring of cycloalkyl can further be selected from following substituting group by 1-3 and replace: C1-C
6Alkyl, halogen ,-OR2、-NHSO
2CF
3、-C(CH
2)
rOR
6、
-(CH
2)
rN(R
2)(R
6),-(CH
2)
r(R
6),-(CH
2)
rC(O)OR
2,-(CH
2)
rC(O)OR
6,
-(CH
2)
rOC(O)R
2,-(CH
2)
rOC(O)R
6,-(CH
2)
rC(O)R
2,-(CH
2)
rC(O)R
6,
-(CH
2)
rC(O)N(R
2)(R
2),-(CH
2)
rC(O)N(R
2)(R
6),-(CH
2)
rN(R
2)C(O)R
2-(CH
2)
rN(R
2)C(O)R
6,-(CH
2)
rN(R6)C(O)R
2,-(CH
2)
rN(R
6)C(O)R
6,
-(CH
2)
rN(R
2)C(O)OR
2,-(CH
2)
rN(R
2)C(O)OR
6,
-(CH
2)
rN(R
6)C(O)OR
2,-(CH
2)
rN(R
6)C(O)OR
6,
-(CH
2)
rN(R
2)C(O)N(R
2)(R
6),-(CH
2)
rN(R
2)C(O)N(R
2)(R
2),
-(CH
2)
rN(R
6)C(O)N(R2)(R
6),(CH
2)
rN(R
2)SO
2R
6,
-(CH
2)
rN(R
2)SO
2R
2,-(CH
2)
rN(R
6)SO
2R
2,CH
2)
rN(R
6)SO
2R
6,
-(CH
2)
rOC(O)N(R
2)(R
6),-(CH
2)
rOC(O)N(R
2)(R
2),
-(CH
2)
rSO
2N(R
2)(R
6),-(CH
2)
rSO
2N(R
2)(R
2),(CH
2)
rSO
2NHC(O)R
6,
-(CH
2)
rSO
2NHC(O)R
2,-(CH
2)
rSO
2NHC(O)OR
6,
-(CH
2)
rSO
2NHC(O)OR
2,-(CH
2)
rC(O)NHC(O)NR
2,
-(CH
2)
rC(O)NHC(O)NR
6,-(CH
2)
rC(O)NHC(O)R
2,
-(CH
2)
rCONHC(O)R
6,-(CH
2)
rCONHSO
2R
6,-(CH
2)
rCONHSO
2R
2,
-(CH
2)
rCONHSO
2N(R
2)(R
2),-(CH
2)
rCONHSO
2N(R
2)(R
6),
-(CH
2)
rN(R
2)SO
2N(R
2)(R
6),-(CH
2)
rN(R
6)SO
2N(R
2)(R
6),
-(CH
2)
rS(O)
mR
6, and-(CH2)
rS(O)
mR
2;
R
3aBe hydrogen, or the C that is randomly replaced by hydroxyl
1-C
6Alkyl;
X is selected from: hydrogen ,-C ≡ N ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl ,-(CH
2)
qOR
2,-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl ,-(CH
2)
qOC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qOC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) R
2,-(CH
2)
qC (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qN (R
2) SO
2N (R
2) (R
2) ,-(CH
2)
qS (O)
mR
2And-(CH
2)
qS (O)
m(CH
2)
tAryl, wherein R
2, (CH
2)
q(CH
2)
tGroup can be randomly by 1-2 C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab, or the 1H-tetrazolium-the 5-base replaces, and aryl is phenyl, naphthyl, pyridine radicals, thiazolyl or 1H-tetrazolium-5-base, these groups can be randomly by 1-3 halogen, a 1-3 OR
2,-CON (R
2) (R
2) ,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
10Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
3-C
7Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl ,-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl contains O, NR
2, S) and-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl), wherein K is O, S (O) m, C (O) NR
2, CH=CH, C ≡ C, N (R
2) C (O), C (O) NR
2, C (O) O or OC (O), and wherein alkyl, R
2, (CH
2)
q(CH
2)
tGroup can be randomly by C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl ,-CONH
2Or carboxylic acid C
1-C
4Arrcostab replaces, and aryl is phenyl, naphthyl, pyridine radicals, 1H-tetrazolium-5-base, thiazolyl, imidazole radicals, indyl, pyrimidine radicals, thiadiazolyl group, pyrazolyl, oxazolyl, isoxazolyl, thienyl, quinolyl, pyrazinyl or isothiazolyl, and these groups can be randomly by 1-3 halogen, a 1-3 OR
2, 1-2-N (R
2) (R
2) ,-C (O) OR
2,-C (O) N (R
2) (R
2), nitro, NHC (O) R
2, cyano group, benzyl, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
R
4And R
5Be hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6Alkyl, wherein substituent group can be 1-5 halogen, a 1-3 hydroxyl, a 1-3 C
1-C
10Alkanoyloxy, a 1-3 C
1-C
6Alkoxyl, phenyl, phenoxy group, 2-furyl, C
1-C
6Alkoxy carbonyl group, S (O) m (C
1-C
6Alkyl); Perhaps R
4And R
5Can lump together formation-(CH
2)
dL
a(CH
2)
e-, L wherein
aBe C (R
2)
2, O, S (O) m or N (R
2), d and e are 1-3 independently, R
2Definition the same;
Wherein x and y are 0,1,2 or 3 independently;
Z is N-R
6aOr O, R here
6aBe hydrogen or C
1-C
6Alkyl;
R
6Be hydrogen, C
1-C
6Alkyl, or (CH
2)
rAryl, wherein alkyl and (CH
2)
vGroup can be randomly by 1-2 OR
2, S (O) mR
2, 1H-tetrazolium-5-base, C (O) OR
2, C (O) N (R
2) (R
2) or SO
2N (R
2) (R
2), N (R
2) C (O) N (R
2) (R
2) replace, and wherein aryl is phenyl, pyridine radicals, 1H-tetrazolium-5-base, triazolyl, imidazole radicals, thiazolyl, pyrazolyl, thiadiazolyl group, imidazolone-1-base, oxadiazole base, benzimidazolyl-2 radicals-Ji, triazoline ketone group, randomly by C
1-C
6Alkyl, C
3-C
6Cycloalkyl, amino or hydroxyl replace;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, trifluoromethyl, phenyl, replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, C (O) OR
2, C
3-C
7Cycloalkyl, C (R
2) (R
2), C (O) N (R
2) (R
2); Perhaps R
7And R
7aCan be independently and R
4And R
5One or two connection in the group is at end nitrogen-atoms and R
7Or R
7aForm alkylidene bridge between the moieties of group, wherein this bridge contains 1-5 carbon atom; Perhaps R
7And R
7aCan C of interconnection formation
3-C
7Cycloalkyl;
M is 0,1 or 2;
N is 1,2 or 3;
Q is 0,1,2,3 or 4;
R is 0,1,2 or 3;
T is 0,1,2 or 3;
V is 0,1 or 2.
8. the chemical compound of claim 7 and pharmaceutically acceptable salt thereof and each diastereomer: wherein:
R
1Be selected from following groups: C
1-C
10Alkyl, aryl (C
1-C
4Alkyl)-, (C
3-C
6Cycloalkyl) (C
1-C
4Alkyl)-, (C
1-C
4Alkyl)-K-(C
1-C
2Alkyl)-, aryl (C
0-C
2Alkyl)-K-(C
1-C
2Alkyl)-and (C
3-C
7Cycloalkyl) (C
0-C
2Alkyl)-K-(C
1-C
2Alkyl)-, wherein K is O, S (O) m, OC (O) or C (O) O, wherein alkyl can be further by 1-7 halogen, S (O) mR
2, a 1-3 OR
2Or C (O) OR
2Replace, aryl is phenyl, naphthyl, indyl, pyridine radicals, benzimidazolyl, azaindolyl, benzothienyl or benzofuranyl, these aryl can be further by 1-2 C
1-C
4Alkyl, a 1-2 halogen, a 1-2 OR
2,-S (O) mR
2, or-C (O) OR
2Replace;
R
2Be hydrogen, C
1-C
6Alkyl and C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
4-C
7Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
3Be phenyl, it is optionally by 1-2 C1-C
6Alkyl, a 1-2 halogen or 1-2 OR2Replace, and can further be selected from following substituting group at its ortho position and replace :-NHSO2CF
3,-(CH
2)
rOR
6,-(CH
2)
rN(R
2)(R
6),-(CH
2)
r(R
6),
-(CH
2)
rC(O)OR
2,-(CH
2)
rC(O)OR
6,-(CH
2)
rOC(O)R
2,
-(CH
2)
rOC(O)R
6,-(CH
2)
rC(O)R
2,-(CH
2)
rC(O)R
6,
-(CH
2)
rC(O)N(R
2)(R
2),-(CH
2)
rC(O)N(R
2)(R
6),-(CH
2)
rN(R
2)C(O)R
2-(CH
2)
rN(R
2)C(O)R
6,-(CH
2)
rN(R
6)C(O)R
2,-(CH
2)
rN(R
6)C(O)R
6,
-(CH
2)
rN(R
2)C(O)OR
2,-(CH
2)
rN(R
2)C(O)OR
6,
-(CH
2)
rN(R
6)C(O)OR
2,-(CH
2)
rN(R
6)C(O)OR
6,
-(CH
2)
rN(R
2)C(O)N(R
2)(R
6),-(CH
2)
rN(R
2)C(O)N(R
2)(R
2),
-(CH
2)
rN(R
6)C(O)N(R
2)(R
6),(CH
2)
rN(R
2)SO
2R
6,
-(CH
2)
rN(R
2)SO
2R
2,-(CH
2)
rN(R
6)SO
2R
2,CH
2)
rN(R
6)SO
2R
6,
-(CH
2)
rOC(O)N(R
2)(R
6),-(CH
2)
rOC(O)N(R
2)(R
2),
-(CH
2)
rSO
2N(R
2)(R
6),-(CH
2)
rSO
2N(R
2)(R
2),(CH
2)
rSO
2NHC(O)R
6,
-(CH
2)
rSO
2NHC(O)R
2,-(CH
2)
rSO
2NHC(O)OR
6,
-(CH
2)
rSO
2NHC(O)OR
2,-(CH
2)
rC(O)NHC(O)NR
2,
-(CH
2)
rC(O)NHC(O)NR
6,-(CH
2)
rC(O)NHC(O)R
2,
-(CH
2)
rCONHC(O)R
6,-(CH
2)
rCONHSO
2R
6,-(CH
2)
rCONHSO
2R
2,
-(CH
2)
rCONHSO
2N(R
2)R
2),-(CH
2)
rCONHSO
2N(R
2)R
6),
-(CH
2)
rN(R
2)SO
2N(R
2)R
6),-(CH
2)
rN(R
6)SO
2N(R
2)R
6),
-(CH
2)
rS(O)
mR
6, and-(CH2)
rS(O)
mR
2;
R
3aBe hydrogen, or C
1-C
4Alkyl;
X is selected from: hydrogen ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl, (CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl ,-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl ,-(CH
2)
qS (O) mR
2And-(CH
2)
qS (O) m (CH
2)
tAryl, wherein R
2Group can be randomly by hydroxyl, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab, or tetrazole radical replacement, and aryl is phenyl, naphthyl, pyridine radicals or 1H-tetrazole radical; These groups can be randomly by 1-2 halogen, a 1-2 OR
2,-CONH
2,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
8Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
5-C
6Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl ,-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl contains O, NR
2, or S) and-(CH
2)
q-K-(CH
2)
t(C
5-C
6Cycloalkyl), wherein K be O or S (O) m and wherein the alkyl gene can be randomly by hydroxyl, carboxyl ,-CONH
2, carboxylic acid C
1-C
4Arrcostab or 1H-tetrazolium-5-base replaces, and aryl is phenyl, naphthyl, pyridine radicals, 1H-tetrazole radical, thiazolyl, imidazole radicals, pyrimidine radicals, thiadiazolyl group, pyrazolyl, oxazolyl, isoxazolyl or thienyl, and these groups can be randomly by 1-3 halogen, a 1-3 OR
2, 1-2-N (R
2) (R
2) ,-C (O) OR
2,-C (O) N (R
2) (R
2), cyano group, a 1-2 C
1-C
4Alkyl, benzyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
R
4And R
5Be hydrogen, C independently
1-C
6Alkyl, or the C that replaces
1-C
6Alkyl, wherein substituent group can be 1-5 halogen, a 1-3 hydroxyl, S (O) m (C
1-C
6Alkyl) or phenyl;
R
6Be hydrogen, C
1-C
6Alkyl, or (CH
2)
vAryl, wherein alkyl and (CH
2)
vGroup can be randomly by 1-2 O (R
2), S (O) mR
2, C (O) OR
2, C (O) N (R
2) (R
2) or SO
2N (R
2) (R
2), N (R
2) C (O) N (R
2) (R
2) replace, and wherein aryl can be phenyl, pyridine radicals, 1H-tetrazolium-5-base, triazolyl, imidazole radicals, thiazolyl, oxadiazole base, pyrazolyl, thiadiazolyl group, phenyl and imidazoles-2-base, randomly by C
1-C
6Alkyl, C
3-C
6Cycloalkyl, amino or hydroxyl replace;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, trifluoromethyl, phenyl, replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, C (O) OR
2, C
3-C
7Cycloalkyl, N (R
2) (R
2), C (O) N (R
2) (R
2); Perhaps R
7And R
7aCan be independently and R
4And R
5A connection in the group is at end nitrogen-atoms and R
7Or R
7aForm alkylidene bridge between the moieties of group, form one 5 yuan or 6 yuan of rings; Perhaps R
7And R
7aCan C of interconnection formation
3Cycloalkyl;
N is 2;
M is 0,1 or 2;
R is 0,1,2 or 3;
Q is 0,1,2 or 3;
T is 0,1,2 or 3;
V is 0,1 or 2.
9. the chemical compound of the claim 7 shown in the Formula B Ib and pharmaceutically acceptable salt thereof and each diastereomer:
Formula BIb is wherein:
R
1Be selected from following groups: C
1-C
10Alkyl, aryl (C
1-C
3Alkyl)-, (C
3-C
7Cycloalkyl) (C
1-C
3Alkyl)-and aryl (C
0-C
1Alkyl)-K-(C
1-C
2Alkyl)-, wherein K is O or S (O) m, and aryl specifically is phenyl, pyridine radicals, naphthyl, indyl, azaindolyl or benzimidazolyl, and these groups can be randomly by 1-2 C
1-C
4Alkyl, a 1-2 halogen, a 1-2 OR
2, S (O) mR
2,-C (O) OR
2Replace;
R
2Be hydrogen, C
1-C
6Alkyl and C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
5-C
7Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
3Be phenyl, they can be randomly by 1-2 C
1-C
6Alkyl, a 1-2 halogen or 1-2 OR
2Replace, and can further be selected from following substituent group at its ortho position and replace;-NHSO
2CF
3,-(CH
2)
rOR
6,-(CH
2)
rN (R
2) (R
6) ,-(CH
2)
r(R
6) ,-(CH
2)
rC (O) OR
6,-(CH
2)
rOC (O) R
2,-(CH
2)
rOC (O) R
6,-(CH
2)
rC (O) R
2,-(CH
2)
rC (O) R
6,-(CH
2)
rC (O) N (R
2) (R
2) ,-(CH
2)
rC (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) R
2-(CH
2)
rN (R
2) C (O) R
6The rN of ,-(CH2) (R6) C (O) R2 ,-(CH2) rN (R
6) C (O) R
6,-(CH
2)
rN (R
2) C (O) OR
2,-(CH
2)
rN (R
2) C (O) OR
6,-(CH
2)
rN (R
6) C (O) OR
2,-(CH
2)
rN (R
6) C (O) OR
6,-(CH
2)
rN (R
2) C (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
rN (R
6) C (O) N (R
2) (R
6), (CH
2)
rN (R
2) SO
2R
6,-(CH
2)
rN (R
2) SO
2R
2,-(CH
2)
rN (R
6) SO
2R
2, CH
2)
rN (R
6) SO
2R
6,-(CH
2)
rOC (O) N (R
2) (R
6) ,-(CH
2)
rOC (O) N (R
2) (R
2) ,-(CH
2)
rSO
2N (R
2) (R
6) ,-(CH
2)
rSO
2N (R
2) (R
2), (CH
2)
rSO
2NHC (O) R
6,-(CH
2)
rSO
2NHC (O) R
2,-(CH
2)
rSO
2NHC (O) OR
6,-(CH
2)
rSO
2NHC (O) OR
2,-(CH
2)
rCONHSO
2R
6,-(CH
2)
rCONHSO
2R
2,-(CH
2)
rS (O)
mR
6And-(CH
2)
rS (O)
mR
2
R
3aBe hydrogen, or C
1-C
4Alkyl;
X is selected from: hydrogen ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl ,-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl ,-(CH
2)
qS (O)
mR
2And ,-(CH
2)
qS (O) m (CH
2)
tAryl, wherein R
2Group can be randomly by hydroxyl, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab, or tetrazole radical replacement, and aryl is phenyl, naphthyl or pyridine radicals, these groups can be further by 1-2 halogen, a 1-2 OR
2,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
8Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
5-C
7Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl and-(CH
2)
q-K-(CH
2)
t(C
5-C
6Cycloalkyl), wherein K is S (O) m, and wherein alkyl group can be randomly by hydroxyl, carboxyl ,-CONH
2, carboxylic acid C
1-C
4Arrcostab 1H-tetrazolium-the 5-base replaces, and aryl specifically is phenyl, naphthyl, pyridine radicals, thiazolyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl or imidazole radicals, and these groups can be randomly by 1-2 halogen, a 1-2 OR
2, 1-2-N (R
2) (R
2) ,-CO (OR
2), a 1-2 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
R
4And R
5Be hydrogen, C independently
1-C
4The C of alkyl, replacement
1-C
3Alkyl, wherein substituent group can be a 1-2 hydroxyl;
R
6Be hydrogen, C
1-C
6Alkyl, or (CH
2)
vAryl, wherein C
1-C
6Alkyl and (CH
2)
vAromatic yl group can be randomly by 1-2 O (R
2), S (O) mR
2, C (O) OR
2, C (O) N (R
2) (R
2) or SO
2N (R
2) (R
2), N (R
2) C (O) N (R
2) (R
2) replace, and wherein aryl specifically is phenyl, pyridine radicals, 1H-tetrazolium-5-base, triazolyl, imidazole radicals, thiazolyl, oxadiazole base, pyrazolyl, thiadiazolyl group, benzimidazolyl-2 radicals-Ji, randomly by C
1-C
6Alkyl, C
3-C
6Cycloalkyl, amino or hydroxyl replace;
A is
Wherein X is 0 or 1;
R
7With
7aBe hydrogen, C independently
1-C
2The C of alkyl, phenyl, replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, perhaps R
7And R
7aCan C of interconnection independently formation
3Cycloalkyl;
M is 0,1 or 2;
R is 0,1,2 or 3;
Q is 0,1,2 or 3;
T is 0,1,2 or 3;
V is 0,1 or 2.
10. the chemical compound of the claim 7 shown in the Formula B Ic and pharmaceutically acceptable salt thereof and each diastereomer:
Formula BIc is wherein:
R
1Be selected from following groups or its orientation isomer (if not explanation):
R
2Be hydrogen, C
1-C
6Alkyl, or C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
5-C
7Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
3Be by being selected from the optional phenyl that replaces of a following substituent group :-NHSO at the ortho position
2CF
3,-(CH
2)
rOR
6,-(CH
2)
r(R
6) ,-(CH
2)
rC (O) OR
2,-(CH
2)
rC (O) OR
6The rOC of ,-(CH2) (O) R2 ,-(CH2) rOC (O) R6 ,-(CH2) rC (O) R2 ,-(CH2) rC (O) R6 ,-(CH
2)
rC (O) N (R
2) (R
2) ,-(CH
2)
rC (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) R
2-(CH
2)
rN (R
2) C (O) R
6,-(CH
2)
rN (R
6) C (O) R
2,-(CH
2)
rN (R
6) C (O) R
6,-(CH
2)
rN (R
2) C (O) OR
2,-(CH
2)
rN (R
2) C (O) OR
6,-(CH
2)
rN (R
6) C (O) OR
2,-(CH
2)
rN (R
6) C (O) OR
6,-(CH
2)
rN (R
2) C (O) N (R
2) (R
6) ,-(CH
2)
rN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
rN (R
6) C (O) N (R
2) (R
6), (CH
2)
rN (R
2) SO
2R
6,-(CH
2)
rN (R
2) SO
2R
2,-(CH
2)
rN (R
6) SO
2R
2, CH
2)
rN (R
6) SO
2R
6,-(CH
2)
rOC (O) N (R
2) (R
6) ,-(CH
2)
rOC (O) N (R
2) (R
2) ,-(CH
2)
rSO
2N (R
2) (R
6) ,-(CH
2)
rSO
2N (R
2) (R
2), (CH
2)
rSO
2NHC (O) R
6,-(CH
2)
rSO
2NHC (O) R
2,-(CH
2)
rSO
2NHC (O) OR
6,-(CH
2)
rSO
2NHC (O) OR
2,-(CH
2)
rCONHSO
2R
6,-(CH
2)
rCONHSO
2R
2,-(CH
2)
rS (O)
mR
6And-(CH
2)
rS (O)
mR
2R
3aBe hydrogen or C
1-C
4Alkyl; X is selected from following groups: hydrogen,
Y is selected from following groups: hydrogen, C
1-C
8Alkyl, (CH
2)
tAryl ,-(CH
2)
qC
5-C
7Cycloalkyl ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl, or-(CH
2)
q-K-(CH
2)
t(C
5-C
6Cycloalkyl), wherein K is S (O) m, and wherein alkyl group can be randomly by hydroxyl, carboxyl, CONH
2, carboxylic acid C
1-C
4Arrcostab or 1H-tetrazolium-5-base replaces, and wherein aryl specifically is phenyl, naphthyl, pyridine radicals, thiazolyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl group, pyrimidine radicals or imidazole radicals, and these groups randomly can be by 1-2 halogen, a 1-2 OR
2, CO (OR)
2, a 1-2 C
1-C
4Alkyl, S (O) mR
2Or 1H-tetrazolium-5-base replaces;
A is selected from following groups:
R
4And R
5Be independently selected from following groups:
-H?-CH
3?-CH
2CH
3
R
6Be hydrogen, C
1-C
5Alkyl or (CH
2)
vAryl, wherein alkyl and (CH
2)
v, group can be randomly by halogen, OR
2, N (R
2) (R
2), C
3-C
6Cycloalkyl, 1H-tetrazolium-5-base, C (O) OR
2, C (O) N (R
2) (R
2), SO
2N (R
2) (R
2) or N (R
2) C (O) N (R
2) (R
2) replace, wherein aryl is selected from following aromatic group and orientation isomer thereof:
Wherein these aromatic groups can be randomly by C
1-C
2Alkyl ,-N (R
2) (R
2) or the hydroxyl replacement;
M is 0,1 or 2;
R is 0,1,2 or 3;
Q is 0 or 1;
T is 0 or 1;
V is 0 or 1.
12. be selected from chemical compound and pharmaceutically acceptable salt and each diastereomer (if not explanation in addition) of following one group claim 7:
Cis, d
1, cis, d
2Trans d
1, trans d
2Cis, d
1, cis, d
2Trans d
1, trans d
2
Cis, d
1, cis, d
2Trans d
1, trans d
2 Cis, d
1, cis, d
2, trans d
1, trans d
2Cis, d
1, cis, d
2, trans d
1, trans d
2 Cis, d
1, cis, d
2Cis d
1, cis, d
2
Cis d
1, cis d
2Cis d
1, cis d
2
13. the chemical compound of general formula CI and pharmaceutically acceptable salt thereof and each diastereomer:
Formula CI is wherein:
R
1Be selected from following groups: C
1-C
10Alkyl, aryl, aryl (C
1-C
6Alkyl), (C
3-C
7Cycloalkyl) (C
1-C
6Alkyl)-, (C
1-C
5Alkyl)-K-(C
1-C
5Alkyl)-, aryl (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-and (C
3-C
7Cycloalkyl) (C
0-C
5Alkyl)-K-(C
1-C
5Alkyl)-, wherein K is O, S (O)
m, N (R
2) C (O), C (O) N (R
2), OC (O), C (O) O ,-CR
2=CR
2-, or-C ≡ C-, wherein aryl is selected from: phenyl, naphthyl, indyl, azaindolyl, pyridine radicals, benzothienyl, benzofuranyl, thiazolyl and benzimidazolyl, and R
2With alkyl can be further by 1-9 halogen, S (O) mR
2a, a 1-3 OR
2aOr C (O) OR
2aReplace, aryl can be further by 1-3 C
1-C
6Alkyl, a 1-3 halogen, a 1-2 OR
2, methylene-dioxy ,-S (O) mR
2, 1-2-CF
3,-OCF
3, nitro ,-N (R
2) C (O) (R
2) ,-C (O) OR
2,-C (O) N (R
2) (R
2) ,-1H-tetrazolium-5-base ,-SO
2N (R
2) (R
2) ,-N (R
2) SO
2Phenyl, or-N (R
2) SO
2R
2Replace;
R
2Be selected from: hydrogen, C
1-C
6Alkyl and C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
3-C
8Cyclic ring randomly contains aerobic, sulfur or NR
3a, R wherein
3aBe hydrogen or C
1-C
6Alkyl randomly can be replaced by hydroxyl;
R
2aBe hydrogen or the C that randomly replaced by hydroxyl
1-C
6Alkyl:
X is selected from: hydrogen ,-C ≡ N ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl ,-(CH
2)
qOR
2,-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl ,-(CH
2)
qOC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qOC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) R
2,-(CH
2)
qC (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qN (R
2) SO
2N (R
2) (R
2) ,-(CH
2)
qS (O) mR
2And-(CH
2)
qS (O) m (CH
2) aryl, wherein R
2, (CH
2)
q(CH
2)
tGroup can be randomly by 1-2 C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab, or the 1H-tetrazolium-the 5-base replaces, and aryl is phenyl, naphthyl, pyridine radicals, thiazolyl or 1H-tetrazolium-5-base, these groups can be randomly by 1-3 halogen, a 1-3 OR
2,-CON (R
2) (R
2) ,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
10Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
3-C
7Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl ,-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl contains O, NR
2, S) and-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl), wherein K is O, S (O) m, C (O) NR
2, CH=CH, C ≡ C, N (R
2) C (O), C (O) NR
2, C (O) O or OC (O), and wherein alkyl, R
2, (CH
2)
q(CH
2)
tGroup can be randomly by C
1-C
4Alkyl, hydroxyl, C
1-C
4Lower alkoxy, carboxyl ,-CONH
2Or carboxylic acid C
1-C
4Arrcostab replaces, and aryl is phenyl, naphthyl, pyridine radicals, 1H-tetrazolium-5-base, thiazolyl, imidazole radicals, indyl, pyrimidine radicals, thiadiazolyl group, pyrazolyl, oxazolyl, isoxazolyl, thienyl, quinolyl, pyrazinyl or isothiazolyl, and these groups can be randomly by 1-3 halogen, a 1-3 OR
2,-C (O) OR
2,-C (O) N (R
2) (R
2), nitro, cyano group, benzyl, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replacement, its condition is if X is a hydrogen, then Y can not be hydrogen;
R
4And R
5Be hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6Alkyl, wherein substituent group can be 1-5 halogen, a 1-3 hydroxyl, a 1-3 C
1-C
10Alkanoyloxy, a 1-3 C
1-C
6Alkoxyl, phenyl, phenoxy group, 2-furyl, C
1-C
6Alkoxy carbonyl group, S (O) m (C
1-C
6Alkyl); Perhaps R
4And R
5Can lump together formation-(CH
2)
dL
a(CH
2)
e-, L wherein
aBe-C (R
2)
2-, O, S (O) m or N (R
2), d and e are 1-3 independently, R
2Definition the same;
Wherein x and y are 0,1,2 or 3 independently;
Z is N-R
6aOr O, R here
6aBe hydrogen or C
1-C
6Alkyl;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, trifluoromethyl, phenyl or replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, C (O) OR
2, C
3-C
7Cycloalkyl, C (R
2) (R
2), C (O) N (R
2) (R
2); Perhaps R
7And R
7aCan be independently and R
4And R
5One or two connection in the group is at end nitrogen-atoms and R
7Or R
7aForm alkylidene bridge between the moieties of group, wherein this bridge contains 1-5 carbon atom; Perhaps R
7And R
7aCan C of interconnection formation
3-C
7Cycloalkyl;
M is 0,1 or 2;
N is 1,2 or 3;
Q is 0,1,2,3 or 4;
T is 0,1,2 or 3.
14. the chemical compound of claim 13 and pharmaceutically acceptable salt thereof and each diastereomer: wherein:
R
1Be selected from following groups: C
1-C
10Alkyl, aryl (C
1-C
4Alkyl)-, (C
3-C
6Cycloalkyl) (C
1-C
4Alkyl)-, (C
1-C
4Alkyl)-K-(C
1-C
2Alkyl)-, aryl (C
0-C
2Alkyl)-K-(C
1-C
2Alkyl)-and (C
3-C
7Cycloalkyl) (C
0-C
2Alkyl)-K-(C
1-C
2Alkyl)-, wherein K is O, S (O) m, OC (O), or C (O) O, alkyl can be further by 1-7 halogen, S (O) mR
2a, a 1-3 OR
2Or C (O) OR
2Replace, aryl is phenyl, naphthyl, indyl, pyridine radicals, benzimidazolyl, azaindolyl, benzothienyl or benzofuranyl, and these aryl can be further by 1-2 C
1-C
4Alkyl, a 1-2 halogen, a 1-2 OR
2, S (O) mR
2,-C (O) OR
2Replace;
R
2Be hydrogen, C
1-C
6Alkyl and C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
4-C
7Cyclic ring randomly contains aerobic, sulfur or NR
3a
R3a is hydrogen or C
1-C
4Alkyl;
X is selected from: hydrogen ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl-(CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl ,-(CH
2)
qS (O) mR
2And-(CH
2)
qS (O) m (CH
2)
tAryl, wherein R
2Group can be randomly by hydroxyl, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab, or tetrazole radical replacement, and aryl is phenyl, naphthyl, pyridine radicals or 1H-tetrazole radical, these groups can be randomly by 1-2 halogen, a 1-2 OR
2,-CONH
2,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
8Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
3-C
6Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl ,-(CH
2)
q-K-(CH
2)
t(C
3-C
7Cycloalkyl contains O, NR
2, S) and-(CH
2)
q-K-(CH
2)
t(C
5-C
6Cycloalkyl), wherein K is O or S (O) m, and wherein alkyl group can be randomly by hydroxyl, carboxyl ,-CONH
2, carboxylic acid C
1-C
4Arrcostab or 1H-tetrazolium-5-base replaces, and aryl is phenyl, naphthyl, pyridine radicals, 1H-tetrazolium-5-base, thiazolyl, imidazole radicals, indyl, pyrimidine radicals, thiadiazolyl group, pyrazolyl, oxazolyl, isoxazolyl or thienyl, and these groups can be randomly by 1-3 halogen, a 1-3 OR
2,-C (O) OR
2,-C (O) N (R
2) (R
2), cyano group, a 1-2 C
1-C
4Alkyl, benzyl-S (O) mR
2, or 1H-tetrazolium-5-base replacement, its condition is, if X is a hydrogen, then Y is not a hydrogen;
R
4And R
5Be hydrogen, C independently
1-C
6The C of alkyl or replacement
1-C
6Alkyl, wherein substituent group can be 1-5 halogen, a 1-3 hydroxyl, S (O) m (C
1-C
6Alkyl) or phenyl;
Wherein x is 0 or 1;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, trifluoromethyl, phenyl, replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, C (O) OR
2, C
5-C
7Cycloalkyl ,-N (R
2) (R
2) ,-C (O) N (R
2) (R
2); Perhaps R
7And R
7aCan be independently and R
4And R
5A connection in the group is at end nitrogen-atoms and R
7Or R
7aForm alkylidene bridge between the moieties of group, form 5 yuan or 6 yuan of rings; Perhaps R
7And R
7aCan C of interconnection formation
3Cycloalkyl;
N is 2;
M is 0,1 or 2;
Q is 0,1,2 or 3;
T is 0,1,2 or 3.
15. the chemical compound of the claim 13 shown in the general formula CIb and pharmaceutically acceptable salt thereof and each diastereomer:
Formula CIb is wherein:
R
1Be selected from following groups: C
1-C
10Alkyl, aryl (C
1-C
3Alkyl)-, (C
3-C
7Cycloalkyl) (C
1-C
3Alkyl)-, and aryl (C
0-C
1Alkyl)-K-(C
1-C
2Alkyl)-, wherein K is that O, S (O) m, aryl are phenyl, pyridine radicals, naphthyl, indyl, azaindolyl or benzimidazolyl, these aryl can be randomly by 1-2 C
1-C
4Alkyl, a 1-2 halogen, a 1-2 OR
2, S (O) mR
2, or-C (O) OR
2Replace;
R
2Be hydrogen, C
1-C
6Alkyl or C
3-C
7Cycloalkyl, and two C wherein
1-C
6When alkyl group appeared on the atom, they can randomly connect, and formed a C
5-C
7Cyclic ring randomly contains aerobic, sulfur or NR
3a
R
3aBe hydrogen, or C
1-C
4Alkyl;
X is selected from: hydrogen ,-(CH
2)
qN (R
2) C (O) R
2,-(CH
2)
qN (R
2) C (O) (CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2(CH
2)
tAryl ,-(CH
2)
qN (R
2) SO
2R
2,-(CH
2)
qN (R
2) C (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qN (R
2) C (O) N (R
2) (R
2) ,-(CH
2)
qC (O) N (R
2) (R
2) ,-(CH
2)
qN (R
2) C (O) OR
2,-(CH
2)
qC (O) N (R
2) (CH
2)
tAryl ,-(CH
2)
qC (O) OR
2,-(CH
2)
qC (O) O (CH
2)
tAryl ,-(CH
2)
qOC (O) R
2,-(CH
2)
qOC (O) (CH
2)
tAryl ,-(CH
2)
qS (O) mR
2And-(CH
2)
qS (O) m (CH
2)
tAryl, wherein R
2Group can be randomly by hydroxyl, carboxyl, CONH
2, S (O) mCH
3, carboxylic acid C
1-C
4Arrcostab, or tetrazole radical replacement, and aryl is phenyl, naphthyl or pyridine radicals, these groups can be further by 1-2 halogen, a 1-2 OR
2,-C (O) OR
2, a 1-3 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replaces;
Y is selected from: hydrogen, C
1-C
8Alkyl ,-(CH
2)
tAryl ,-(CH
2)
q(C
5-C
7Cycloalkyl) ,-(CH
2)
q-K-(C
1-C
6Alkyl) ,-(CH
2)
q-K-(CH
2)
tAryl and-(CH
2)
q-K-(CH
2)
t(C
5-C
6Cycloalkyl), wherein K is S (O) m, and wherein alkyl group can be randomly by hydroxyl, carboxyl ,-CONH
2Or carboxylic acid C
1-C
4Arrcostab or 1H-tetrazolium-the 5-base replaces, and aryl is phenyl, naphthyl, pyridine radicals, thiazolyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl or imidazole radicals, and these groups can be randomly by 1-2 halogen, a 1-3 OR
2, 1-2-N (R
2) (R
2), CO (OR
2), a 1-2 C
1-C
4Alkyl ,-S (O) mR
2, or 1H-tetrazolium-5-base replacement, its condition is if X is a hydrogen, then Y is not a hydrogen;
R
4And R
5Be hydrogen, C independently
1-C
4The C of alkyl or replacement
1-C
3Alkyl, wherein substituent group can be a 1-2 hydroxyl;
Wherein x be 0 or or 1;
R
7And R
7aBe hydrogen, C independently
1-C
6The C of alkyl, phenyl, replacement
1-C
6Alkyl, wherein substituent group is imidazole radicals, phenyl, indyl, p-hydroxybenzene, OR
2, S (O) mR
2, perhaps R
7And R
7aCan C of interconnection formation
3Cycloalkyl;
M is 0,1 or 2;
Q is 0,1,2 or 3;
T is 0,1,2 or 3.
16. the chemical compound of the claim 13 shown in the general formula CIc and pharmaceutically acceptable salt thereof and each diastereomer:
Formula CIc wherein
Its condition is if X is a hydrogen, and then Y can not be a hydrogen;
R
4And R
5Be independently selected from following groups:
-H?????????-CH
3????????-CH
2CH
3
17. the Stereoselective chemical compound of the claim 13 shown in the following formula:
R wherein
1, R
4, R
5, A, X, Y and n definition as described in the claim 13.
19. the interior compositions of producing or discharging that is used for increasing human body or animal body growth hormone, said composition comprises the chemical compound of the claim 1 of a kind of inert carrier and a kind of effective dose.
20. the interior compositions of producing or discharging that is used for increasing human body or animal body bio-hormone, said composition comprises the chemical compound of the claim 1 of a kind of inert carrier, a kind of effective dose, and a kind of other growth hormone succagoga.
21. the compositions of claim 20, wherein this other bio-hormone succagoga is selected from following one group: analog, IGF-1 and the IGF-2 of growth hormone-releasing peptide GHRP-6, growth hormone-releasing peptide GHRP-2, growth hormone-releasing peptide GHRP-1, B-HT 920, somatotropin releasing factor, somatotropin releasing factor.
22. one kind is used for the treatment of osteoporotic compositions, said composition comprises the combination of compounds of a kind of bisphosphonate and a kind of claim 1.
23. the compositions of claim 22, wherein this di 2 ethylhexyl phosphonic acid phosphate compounds is alendronate.
24. a method of giving birth to level of growth hormone in increasing in human body or the animal body, this method comprise the chemical compound of human body or animal body being used a kind of claim 1 of effective dose.
25. one kind increases domestic animal feed efficient, promotes domestic animal growth, increase domestic animal milk amount and improves domestic animal carcass method for quality, this method comprises the chemical compound of domestic animal being used a kind of claim 1 of effective dose.
26. the method for the treatment of or preventing to be selected from following disease, osteoporosis, katabolism disease, immunodeficiency comprise T
4/ T
8Cell is than individual immunity defective on the low side, Hip Fracture, old flesh skeletal injury, people and children growth hormone deficiency, obesity, because evil matter disease that chronic disease such as AIDS or cancer cause and protein loss, and treatment needs the patient's who is coming from major operation, various damage or burn rehabilitation of the above-mentioned disease of treatment method, and this method comprises the chemical compound of the patient being used the claim 1 of effective dose.
27. the osteoporotic method of treatment, this method comprises suffering from the combination of compounds that osteoporotic patient uses a kind of bisphosphonate and a kind of claim 1.
28. the method for claim 27, wherein this di 2 ethylhexyl phosphonic acid phosphate compounds is alendronate.
29. comprising, the preparation method of the chemical compound of claim 1, this method make down facial 4 chemical compound:
Chemical compound reaction with formula 5 or formula 6:
Or
Obtain the chemical compound of formula I or formula 7:
Or
R wherein
1, R
3, R
4, R
5, A, W, X, Y and n definition according to claim 1, L is the protecting group that will remove subsequently if present, and if desired, can form salt.
30. comprising, the preparation method of the chemical compound of claim 1, this method make down facial 12 or the chemical compound of 12a:
Or
Chemical compound reaction with formula 2:
Obtain the chemical compound of formula I or 7:
Or
R wherein
1, R
3, R
4, R
5, A, W, X, Y and n definition according to claim 1, L is the protecting group that will remove subsequently if present, and if desired, can form salt.
Applications Claiming Priority (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14944193A | 1993-11-09 | 1993-11-09 | |
US08/149,441 | 1993-11-09 | ||
US16514993A | 1993-12-10 | 1993-12-10 | |
US08/165,149 | 1993-12-10 | ||
US17344993A | 1993-12-23 | 1993-12-23 | |
US08/173,449 | 1993-12-23 | ||
US08/323,998 | 1994-10-17 | ||
US08/323,994 US5494919A (en) | 1993-11-09 | 1994-10-17 | 2-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone |
US08/323,994 | 1994-10-17 | ||
US08/323,988 | 1994-10-17 | ||
US08/323,998 US5492920A (en) | 1993-12-10 | 1994-10-17 | Piperidine, pyrrolidine and hexahydro-1H-azepines promote release of growth hormone |
US08/323,988 US5492916A (en) | 1993-12-23 | 1994-10-17 | Di- and tri-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1174504A true CN1174504A (en) | 1998-02-25 |
Family
ID=27558364
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN94194738A Pending CN1174504A (en) | 1993-11-09 | 1994-11-07 | Piperidines, pyrrolidines and hexahydro -1H -azepines promote release of growth hormone |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP0739204A4 (en) |
JP (1) | JPH10506091A (en) |
KR (1) | KR960705808A (en) |
CN (1) | CN1174504A (en) |
AU (1) | AU1172995A (en) |
BG (1) | BG100555A (en) |
BR (1) | BR9408019A (en) |
CA (1) | CA2175218A1 (en) |
CZ (1) | CZ134296A3 (en) |
FI (1) | FI961951A (en) |
HU (1) | HUT74733A (en) |
LV (1) | LV11525B (en) |
NO (1) | NO961865L (en) |
PL (1) | PL322706A1 (en) |
SK (1) | SK56296A3 (en) |
WO (1) | WO1995013069A1 (en) |
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CN114805305A (en) * | 2022-04-20 | 2022-07-29 | 成都诺和晟泰生物科技有限公司 | Compound and application thereof |
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- 1994-11-07 WO PCT/US1994/012816 patent/WO1995013069A1/en not_active Application Discontinuation
- 1994-11-07 BR BR9408019A patent/BR9408019A/en not_active Application Discontinuation
- 1994-11-07 PL PL94322706A patent/PL322706A1/en unknown
- 1994-11-07 CN CN94194738A patent/CN1174504A/en active Pending
- 1994-11-07 CZ CZ961342A patent/CZ134296A3/en unknown
- 1994-11-07 AU AU11729/95A patent/AU1172995A/en not_active Abandoned
- 1994-11-07 KR KR1019960702427A patent/KR960705808A/en not_active Application Discontinuation
-
1996
- 1996-05-02 BG BG100555A patent/BG100555A/en unknown
- 1996-05-08 NO NO961865A patent/NO961865L/en unknown
- 1996-05-08 FI FI961951A patent/FI961951A/en unknown
- 1996-05-22 LV LVP-96-151A patent/LV11525B/en unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114805305A (en) * | 2022-04-20 | 2022-07-29 | 成都诺和晟泰生物科技有限公司 | Compound and application thereof |
CN114805305B (en) * | 2022-04-20 | 2024-04-26 | 成都诺和晟泰生物科技有限公司 | Compound and application thereof |
Also Published As
Publication number | Publication date |
---|---|
FI961951A0 (en) | 1996-05-08 |
CZ134296A3 (en) | 1996-12-11 |
SK56296A3 (en) | 1997-02-05 |
HUT74733A (en) | 1997-02-28 |
EP0739204A1 (en) | 1996-10-30 |
WO1995013069A1 (en) | 1995-05-18 |
EP0739204A4 (en) | 2000-03-15 |
NO961865D0 (en) | 1996-05-08 |
HU9601230D0 (en) | 1996-07-29 |
KR960705808A (en) | 1996-11-08 |
FI961951A (en) | 1996-05-08 |
BR9408019A (en) | 1997-08-26 |
JPH10506091A (en) | 1998-06-16 |
LV11525A (en) | 1996-10-20 |
BG100555A (en) | 1996-10-31 |
PL322706A1 (en) | 1998-02-16 |
NO961865L (en) | 1996-07-08 |
CA2175218A1 (en) | 1995-05-18 |
AU1172995A (en) | 1995-05-29 |
LV11525B (en) | 1997-02-20 |
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